Integrin receptor antagonists

ABSTRACT

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors αvβ3, αvβ5, and/or αvβ6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present invention is related to U.S. provisional applicationsSerial No. 60/069,899, filed Dec. 17, 1997; 60/083,209, filed Apr. 27,1998; 60/092,622, filed Jul. 13, 1998; and 60/108,063, filed Nov. 12,1998; the contents of all of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds and derivativesthereof, their synthesis, and their use as integrin receptorantagonists. More particularly, the compounds of the present inventionare antagonists of the integrin receptors αvβ3, αvβ5, and/or αvβ6 andare useful for inhibiting bone resorption, treating and preventingosteoporosis, and inhibiting vascular restenosis, diabetic retinopathy,macular degeneration, angiogenesis, atherosclerosis, inflammation, woundhealing, viral disease, tumor growth, and metastasis.

BACKGROUND OF THE INVENTION

[0003] It is believed that a wide variety of disease states andconditions can be mediated by acting on integrin receptors and thatintegrin receptor antagonists represent a useful class of drugs.Integrin receptors are heterodimeric transmembrane receptors throughwhich cells attach and communicate with extracellular matrices and othercells. (See S. B. Rodan and G. A. Rodan, “Integrin Function InOsteoclasts”, Journal of Endocrinology, Vol. 154, S47-S56 (1997), whichis incorporated by reference herein in its entirety).

[0004] In one aspect of the present invention, the compounds herein areuseful for inhibiting bone resorption. Bone resorption is mediated bythe action of cells known as osteoclasts. Osteoclasts are largemultinucleated cells of up to about 400 mm in diameter that resorbmineralized tissue, chiefly calcium carbonate and calcium phosphate, invertebrates. Osteoclasts are actively motile cells that migrate alongthe surface of bone, and can bind to bone, secrete necessary acids andproteases, thereby causing the actual resorption of mineralized tissuefrom the bone. More specifically, osteoclasts are believed to exist inat least two physiological states, namely. the secretory state and themigratory or motile state. In the secretory state, osteoclasts are flat,attach to the bone matrix via a tight attachment zone (sealing zone),become highly polarized, form a ruffled border, and secrete lysosomalenzymes and protons to resorb bone. The adhesion of osteoclasts to bonesurfaces is an important initial step in bone resorption. In themigratory or motile state, the osteoclasts migrate across bone matrixand do not take part in resorption until they again attach to bone.

[0005] Integrins are involved in osteoclast attachment, activation andmigration. The most abundant integrin in osteoclasts, e.g., in rat,chicken, mouse and human osteoclasts, is an integrin receptor known asαvβ3, which is thought to interact in bone with matrix proteins thatcontain the RGD sequence. Antibodies to αvβ3 block bone resorption invitro indicating that this integrin plays a key role in the resorptiveprocess. There is increasing evidence to suggest that αvβ3 ligands canbe used effectively to inhibit osteoclast mediated bone resorption invivo in mammals.

[0006] The current major bone diseases of public concern areosteoporosis, hypercalcemia of malignancy, osteopenia due to bonemetastases, periodontal disease, hyperparathyroidism, periarticularerosions in rheumatoid arthritis, Paget's disease,immobilization-induced osteopenia, and glucocorticoid-inducedosteoporosis. All of these conditions are characterized by bone loss,resulting from an imbalance between bone resorption, i.e. breakdown, andbone formation, which continues throughout life at the rate of about 14%per year on the average. However, the rate of bone turnover differs fromsite to site; for example, it is higher in the trabecular bone of thevertebrae and the alveolar bone in the jaws than in the cortices of thelong bones. The potential for bone loss is directly related to turnoverand can amount to over 5% per year in vertebrae immediately followingmenopause, a condition which leads to increased fracture risk.

[0007] In the United States, there are currently about 20 million peoplewith detectable fractures of the vertebrae due to osteoporosis. Inaddition, there are about 250,000 hip fractures per year attributed toosteoporosis. This clinical situation is associated with a 12% mortalityrate within the first two years, while 30% of the patients requirenursing home care after the fracture.

[0008] Individuals suffering from all the conditions listed above wouldbenefit from treatment with agents which inhibit bone resorption.

[0009] Additionally, αvβ3 ligands have been found to be useful intreating and/or inhibiting restenosis, i.e. recurrence of stenosis aftercorrective surgery on the heart valve, atherosclerosis, diabeticretinopathy, macular degeneration, and angiogenesis, i.e. formation ofnew blood vessels, and inhibiting viral disease. Moreover, it has beenpostulated that the growth of tumors depends on an adequate bloodsupply, which in turn is dependent on the growth of new vessels into thetumor; thus, inhibition of angiogenesis can cause tumor regression inanimal models (See Harrison's Principles of Internal Medicine, 12th ed.,1991, which is incorporated by reference herein in its entirety).Therefore, αvβ3 antagonists which inhibit angiogenesis can be useful inthe treatment of cancer by inhibiting tumor growth (See, e.g., Brooks etal., Cell, 79:1157-1164 (1994), which is incorporated by referenceherein in its entirety).

[0010] Moreover, compounds of this invention can also inhibitneovascularization by acting as antagonists of the integrin receptor,αvβ5. A monoclonal antibody for αvβ5 has been shown to inhibitVEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoicmembrane model (See M. C. Friedlander, et.al., Science 270:1500-1502(1995), which is incorporated by reference herein in its entirety).Thus, compounds that antagonize αvβ5 are useful for treating andpreventing macular degeneration, diabetic retinopathy, tumor growth, andmetastasis.

[0011] Additionally, compounds of the instant invention can inhibitangiogenesis and inflammation by acting as antagonists of the integrinreceptor, αvβ6, which is expressed during the later stages of woundhealing and remains expressed until the wound is closed (SeeChristofidou-Solomidou, et al., “Expression and Function of EndothelialCell αv Integrin Receptors in Wound-Induced Human Angiogenesis in HumanSkin/SCID Mice Chimeras, American Journal of Pathology, Vol. 151, No. 4,pp. 975-983 (October 1997), which is incorporated by reference herein inits entirety). It is postulated that αvβ6 plays a role in the remodelingof the vasculature during the later stages of angiogenesis. Also, αvβ6participates in the modulation of epithelial inflammation and is inducedin response to local injury or inflammation (See Xiao-Zhu Huang, et al.,“Inactivation of the Integrin β6 Subunit Gene Reveals a Role ofEpithelial Integrins in Regulating Inflammation in the Lungs and Skin,”Journal of Cell Biology, Vol. 133, No.4, pp. 921-928 (May 1996), whichis incorporated by reference herein in its entirety). Accordingly,compounds that antagonize αvβ6 are useful in treating or preventingcancer by inhibiting tumor growth and metastasis.

[0012] In addition, certain compounds of this invention antagonize boththe αvβ3 and αvβ5 receptors. These compounds, referred to as “dualαvβ3/αvβ5 antagonists,” are useful for inhibiting bone resorption,treating and preventing osteoporosis, and inhibiting vascularrestenosis, diabetic retinopathy, macular degeneration, angiogenesis,atherosclerosis, inflammation, viral disease, tumor growth, andmetastasis.

[0013] In addition, certain compounds of this invention are useful asmixed αvβ3, αvβ5, and αvβ6 receptor antagonists.

[0014] It is therefore an object of the present invention to providecompounds which are useful as integrin receptor antagonists.

[0015] It is another object of the present invention to providecompounds which are useful as αvβ3 receptor antagonists.

[0016] It is another object of the present invention to providecompounds which are useful as αvβ5 receptor antagonists.

[0017] It is another object of the present invention to providecompounds which are useful as αvβ6 receptor antagonists.

[0018] It is another object of the present invention to providecompounds which are useful as dual αvβ3/αvβ5 receptor antagonists.

[0019] It is another object of the present invention to providecompounds which are useful as mixed αvβ3, αvβ5, and αvβ6 receptorantagonists.

[0020] It is another object of the present invention to providepharmaceutical compositions comprising integrin receptor antagonists.

[0021] It is another object of the present invention to provide methodsfor making the pharmaceutical compositions of the present invention.

[0022] It is another object of the present invention to provide methodsfor eliciting an integrin receptor antagonizing effect in a mammal inneed thereof by administering the compounds and pharmaceuticalcompositions of the present invention.

[0023] It is another object of the present invention to providecompounds and pharmaceutical compositions useful for inhibiting boneresorption, restenosis, atherosclerosis, inflammation, viral disease,diabetic retinopathy, macular degeneration, angiogenesis, tumor growth,and metastasis.

[0024] It is another object of the present invention to providecompounds and pharmaceutical compositions useful for treatingosteoporosis.

[0025] It is another object of the present invention to provide methodsfor inhibiting bone resorption, restenosis, atherosclerosis,inflammation, viral disease, diabetic retinopathy, macular degeneration,angiogenesis, tumor growth, and metastasis.

[0026] It is another object of the present invention to provide methodsfor treating osteoporosis.

[0027] These and other objects will become readily apparent from thedetailed description which follows.

SUMMARY OF THE INVENTION

[0028] The present invention relates to compounds of the formula

[0029] wherein X is selected from the group consisting of

[0030] a 5- or 6-membered monocyclic aromatic or nonaromatic ring systemhaving 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting ofN, O, and S wherein the ring nitrogen atoms are unsubstituted orsubstituted with one R¹ substituent and the ring carbon atoms areunsubstituted or substituted with one or two R¹ substituents, and

[0031] a 9- to 14-membered polycyclic ring system, wherein one or moreof the rings is aromatic, and wherein the polycyclic ring system has 0,1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, andS, and wherein the ring nitrogen atoms are unsubstituted or substitutedwith one R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

[0032] Y is selected from the group consisting of

[0033] —(CH₂)_(m),

[0034] —(CH₂)_(m)—O—(CH₂)_(n)—,

[0035] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—,

[0036] —(CH₂)_(m)—S—(CH₂)_(n)—,

[0037] —(CH₂)_(m)—SO—(CH₂)_(n)—,

[0038] —(CH₂)_(m)—SO₂—(CH₂)_(n)—,

[0039] —(CH₂)_(m)—O—(CH₂)_(n)—O—(CH₂)_(p)—,

[0040] —(CH₂)_(m)—O—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,

[0041] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,

[0042] —(CH₂)_(m)—O—(CH₂)_(n)—S—(CH₂)_(p)—,

[0043] —(CH₂)_(m)—S—(CH₂)_(n)—S—(CH₂)_(p)—,

[0044] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—S—(CH₂)_(p)—,

[0045] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—O—(CH₂)_(p)—,

[0046] —(CH₂)_(m)—S—(CH₂)_(n)—O—(CH₂)_(p)—, and

[0047] —(CH₂)_(m)—S—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,

[0048] wherein any methylene (CH₂) carbon atom in Y, other than in R⁴,can be substituted by one or two R³ substituents;

[0049] Z is selected from the group consisting of

[0050] —CH₂CH₂— and —CH═CH—, wherein either carbon atom can besubstituted by one or two R³ substituents;

[0051] R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino,C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(p)amino, (C₁₋₆ alkyl)_(p)aminoC₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonylC₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl,C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈alkyl)_(p)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈alkyl)_(p)aminocarbonyloxy, (aryl C₁₋₈ alkyl)_(p)amino, (aryl)_(p)amino,aryl C₁₋₈ alkylsulfonylamino, and C₁₋₈ alkylsulfonylamino;

[0052] or two R¹ substituents, when on the same carbon atom, are takentogether with the carbon atom to which they are attached to form acarbonyl group;

[0053] each R³ is independently selected from the group consisting of

[0054] hydrogen,

[0055] aryl,

[0056] C₁₋₁₀ alkyl,

[0057] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0058] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0059] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0060] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0061] aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—,

[0062] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0063] halogen,

[0064] hydroxyl,

[0065] oxo,

[0066] trifluoromethyl,

[0067] C₁₋₈ alkylcarbonylamino,

[0068] aryl C₁₋₅ alkoxy,

[0069] C₁₋₅ alkoxycarbonyl,

[0070] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0071] C₁₋₆ alkylcarbonyloxy,

[0072] C₃₋₈ cycloalkyl,

[0073] (C₁₋₆ alkyl)_(p)amino,

[0074] amino C₁₋₆ alkyl,

[0075] arylaminocarbonyl,

[0076] aryl C₁₋₅ alkylaminocarbonyl,

[0077] aminocarbonyl,

[0078] aminocarbonyl C₁₋₆ alkyl,

[0079] hydroxycarbonyl,

[0080] hydroxycarbonyl C₁₋₆ alkyl,

[0081] HC≡C—(CH₂)_(t)—,

[0082] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0083] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0084] aryl-C≡C—(CH₂)_(t)—,

[0085] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0086] CH₂═CH—(CH₂)_(t)—,

[0087] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0088] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0089] aryl-CH═CH—(CH₂)_(t)—,

[0090] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0091] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0092] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0093] C₁₋₆ alkoxy,

[0094] aryl C₁₋₆ alkoxy,

[0095] aryl C₁₋₆ alkyl,

[0096] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0097] (aryl)_(p)amino,

[0098] (aryl)_(p)amino C₁₋₆ alkyl,

[0099] (aryl C₁₋₆ alkyl)_(p)amino,

[0100] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0101] arylcarbonyloxy,

[0102] aryl C₁₋₆ alkylcarbonyloxy,

[0103] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0104] C₁₋₈ alkylsulfonylamino,

[0105] arylsulfonylamino,

[0106] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0107] arylsulfonylamino C₁₋₆ alkyl,

[0108] aryl C₁₋₆ alkylsulfonylamino,

[0109] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0110] C₁₋₈ alkoxycarbonylamino,

[0111] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0112] aryloxycarbonylamino C₁₋₈ alkyl,

[0113] aryl C₁₋₈ alkoxycarbonylamino,

[0114] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0115] C₁₋₈ alkylcarbonylamino,

[0116] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0117] arylcarbonylamino C₁₋₆ alkyl,

[0118] aryl C₁₋₆ alkylcarbonylamino,

[0119] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0120] aminocarbonylamino C₁₋₆ alkyl,

[0121] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0122] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0123] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0124] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0125] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0126] aminosulfonylamino C₁₋₆ alkyl,

[0127] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0128] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0129] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0130] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0131] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0132] C₁₋₆ alkylsulfonyl,

[0133] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0134] arylsulfonyl C₁₋₆ alkyl,

[0135] aryl C₁₋₆ alkylsulfonyl,

[0136] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0137] C₁₋₆ alkylcarbonyl,

[0138] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0139] arylcarbonyl C₁₋₆ alkyl,

[0140] aryl C₁₋₆ alkylcarbonyl,

[0141] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0142] C₁₋₆ alkylthiocarbonylamino,

[0143] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0144] arylthiocarbonylamino C₁₋₆ alkyl,

[0145] aryl C₁₋₆ alkylthiocarbonylamino,

[0146] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0147] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0148] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0149] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and

[0150] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl;

[0151] or two R³ substituents, when on the same carbon atom are takentogether with the carbon atom to which they are attached to form acarbonyl group or a cyclopropyl group,

[0152] wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

[0153] each R⁴ is independently selected from the group consisting of

[0154] hydrogen,

[0155] aryl,

[0156] aminocarbonyl,

[0157] C₃₋₈ cycloalkyl,

[0158] amino C₁₋₆ alkyl,

[0159] (aryl)_(p)aminocarbonyl,

[0160] (aryl C₁₋₅ alkyl)_(p)aminocarbonyl,

[0161] hydroxycarbonyl C₁₋₆ alkyl,

[0162] C₁₋₈ alkyl,

[0163] aryl C₁₋₆ alkyl,

[0164] (C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,

[0165] (aryl C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,

[0166] C₁₋₈ alkylsulfonyl,

[0167] C₁₋₈ alkoxycarbonyl,

[0168] aryloxycarbonyl,

[0169] aryl C₁₋₈ alkoxycarbonyl,

[0170] C₁₋₈ alkylcarbonyl,

[0171] arylcarbonyl,

[0172] aryl C₁₋₆ alkylcarbonyl,

[0173] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0174] aminosulfonyl,

[0175] C₁₋₈ alkylaminosulfonyl,

[0176] (aryl)_(p)aminosulfonyl,

[0177] (aryl C₁₋₈ alkyl)_(p)aminosulfonyl,

[0178] arylsulfonyl,

[0179] arylC₁₋₆ alkylsulfonyl,

[0180] C₁₋₆ alkylthiocarbonyl,

[0181] arylthiocarbonyl, and

[0182] aryl C₁₋₆ alkylthiocarbonyl,

[0183] wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

[0184] R⁵ and R⁶ are each independently selected from the groupconsisting of

[0185] hydrogen,

[0186] C₁₋₁₀ alkyl,

[0187] aryl,

[0188] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0189] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0190] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0191] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0192] aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—,

[0193] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0194] halogen,

[0195] hydroxyl,

[0196] C₁₋₈ alkylcarbonylamino,

[0197] aryl C₁₋₅ alkoxy,

[0198] C₁₋₅ alkoxycarbonyl,

[0199] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0200] C₁₋₆ alkylcarbonyloxy,

[0201] C₃₋₈ cycloalkyl,

[0202] (C₁₋₆ alkyl)_(p)amino,

[0203] amino C₁₋₆ alkyl,

[0204] arylaminocarbonyl,

[0205] aryl C₁₋₅ alkylaminocarbonyl,

[0206] aminocarbonyl,

[0207] aminocarbonyl C₁₋₆ alkyl,

[0208] hydroxycarbonyl,

[0209] hydroxycarbonyl C₁₋₆ alkyl,

[0210] HC≡C—(CH₂)_(t)—,

[0211] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0212] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0213] aryl-C≡C—(CH₂)_(t)—,

[0214] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0215] CH₂═CH—(CH₂)_(t)—,

[0216] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0217] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0218] aryl-CH═CH—(CH₂)_(t)—,

[0219] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0220] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0221] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0222] C₁₋₆ alkoxy,

[0223] aryl C₁₋₆ alkoxy,

[0224] aryl C₁₋₆ alkyl,

[0225] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0226] (aryl)_(p)amino,

[0227] (aryl)_(p)amino C₁₋₆ alkyl,

[0228] (aryl C₁₋₆ alkyl)_(p)amino,

[0229] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0230] arylcarbonyloxy,

[0231] aryl C₁₋₆alkylcarbonyloxy,

[0232] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0233] C₁₋₈ alkylsulfonylamino,

[0234] arylsulfonylamino,

[0235] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0236] arylsulfonylamino C₁₋₆ alkyl,

[0237] aryl C₁₋₆ alkylsulfonylamino,

[0238] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0239] C₁₋₈ alkoxycarbonylamino,

[0240] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0241] aryloxycarbonylamino C₁₋₈ alkyl,

[0242] aryl C₁₋₈ alkoxycarbonylamino,

[0243] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0244] C₁₋₈ alkylcarbonylamino,

[0245] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0246] arylcarbonylamino C₁₋₆ alkyl,

[0247] aryl C₁₋₆ alkylcarbonylamino,

[0248] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0249] aminocarbonylamino C₁₋₆ alkyl,

[0250] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0251] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0252] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0253] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0254] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0255] aminosulfonylamino C₁₋₆ alkyl,

[0256] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0257] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0258] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0259] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0260] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0261] C₁₋₆ alkylsulfonyl,

[0262] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0263] arylsulfonyl C₁₋₆ alkyl,

[0264] aryl C₁₋₆ alkylsulfonyl,

[0265] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0266] C₁₋₆ alkylcarbonyl,

[0267] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0268] arylcarbonyl C₁₋₆ alkyl,

[0269] aryl C₁₋₆ alkylcarbonyl,

[0270] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0271] C₁₋₆ alkylthiocarbonylamino,

[0272] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0273] arylthiocarbonylamino C₁₋₆ alkyl,

[0274] aryl C₁₋₆ alkylthiocarbonylamino,

[0275] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0276] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0277] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0278] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and

[0279] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl;

[0280] or R⁵ and R⁶ are taken together with the carbon atom to whichthey are attached to form a carbonyl group,

[0281] wherein any of the alkyl groups of R⁵ or R⁶ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁵ and R⁶ are selected such that in the resultantcompound the carbon atom to which R⁵ and R⁶ are attached is itselfattached to no more than one heteroatom;

[0282] R⁷ and R⁸ are each independently selected from the groupconsisting of

[0283] hydrogen,

[0284] C₁₋₁₀ alkyl,

[0285] aryl,

[0286] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0287] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0288] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0289] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0290] aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—,

[0291] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0292] halogen,

[0293] hydroxyl,

[0294] C₁₋₈ alkylcarbonylamino,

[0295] aryl C₁₋₅ alkoxy,

[0296] C₁₋₅ alkoxycarbonyl,

[0297] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0298] C₁₋₆ alkylcarbonyloxy,

[0299] C₃₋₈ cycloalkyl,

[0300] (C₁₋₆ alkyl)_(p)amino,

[0301] amino C₁₋₆ alkyl,

[0302] arylaminocarbonyl,

[0303] aryl C₁₋₅ alkylaminocarbonyl,

[0304] aminocarbonyl,

[0305] aminocarbonyl C₁₋₆ alkyl,

[0306] hydroxycarbonyl,

[0307] hydroxycarbonyl C₁₋₆ alkyl,

[0308] HC≡C—(CH₂)_(t)—,

[0309] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0310] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0311] aryl-C≡C—(CH₂)_(t)—,

[0312] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0313] CH₂═CH—(CH₂)_(t)—,

[0314] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0315] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0316] aryl-CH═CH—(CH₂)_(t)—,

[0317] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0318] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0319] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0320] C₁₋₆ alkoxy,

[0321] aryl C₁₋₆ alkoxy,

[0322] aryl C₁₋₆alkyl,

[0323] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0324] (aryl)_(p)amino,

[0325] (aryl)_(p)amino C₁₋₆ alkyl,

[0326] (aryl C₁₋₆ alkyl)_(p)amino,

[0327] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0328] arylcarbonyloxy,

[0329] aryl C₁₋₆ alkylcarbonyloxy,

[0330] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0331] C₁₋₈ alkylsulfonylamino,

[0332] arylcarbonylamino,

[0333] arylsulfonylamino,

[0334] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0335] arylsulfonylamino C₁₋₆ alkyl,

[0336] aryl C₁₋₆ alkylsulfonylamino,

[0337] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0338] C₁₋₈ alkoxycarbonylamino,

[0339] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0340] aryloxycarbonylamino C₁₋₈ alkyl,

[0341] aryl C₁₋₈ alkoxycarbonylamino,

[0342] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0343] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0344] arylcarbonylamino C₁₋₆ alkyl,

[0345] aryl C₁₋₆ alkylcarbonylamino,

[0346] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0347] aminocarbonylamino C₁₋₆ alkyl,

[0348] arylaminocarbonylamino,

[0349] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0350] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0351] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0352] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0353] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0354] aminosulfonylamino C₁₋₆ alkyl,

[0355] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0356] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0357] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0358] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0359] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0360] C₁₋₆ alkylsulfonyl,

[0361] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0362] arylsulfonyl C₁₋₆ alkyl,

[0363] aryl C₁₋₆ alkylsulfonyl,

[0364] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0365] C₁₋₆ alkylcarbonyl,

[0366] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0367] arylcarbonyl C₁₋₆ alkyl,

[0368] aryl C₁₋₆ alkylcarbonyl,

[0369] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0370] C₁₋₆ alkylthiocarbonylamino,

[0371] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0372] arylthiocarbonylamino C₁₋₆ alkyl,

[0373] aryl C₁₋₆ alkylthiocarbonylamino,

[0374] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0375] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0376] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0377] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl,

[0378] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, and

[0379] C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino,

[0380] wherein any of the alkyl groups of R⁷ and R⁸ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom;

[0381] R⁹ is selected from the group consisting of

[0382] hydrogen,

[0383] C₁₋₈ alkyl,

[0384] aryl,

[0385] aryl C₁₋₈ alkyl,

[0386] C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

[0387] aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

[0388] C₁₋₈ alkylaminocarbonylmethylene, and

[0389] C₁₋₈ dialkylaminocarbonylmethylene;

[0390] wherein

[0391] each m is independently an integer from 0 to 6;

[0392] each n is independently an integer from 0 to 6;

[0393] each p is independently an integer from 0 to 2;

[0394] each r is independently an integer from 1 to 3;

[0395] each s is independently an integer from 0 to 3; and

[0396] each t is independently an integer from 0 to 3;

[0397] and the pharmaceutically acceptable salts thereof.

[0398] The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

[0399] The present invention also relates to methods for making thepharmaceutical compositions of the present invention.

[0400] The present invention also relates to methods for eliciting anintegrin receptor antagonizing effect in a mammal in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention.

[0401] The present invention also relates to methods for inhibiting boneresorption, restenosis, atherosclerosis, inflammation, viral disease,diabetic retinopathy, macular degeneration, angiogenesis, wound healing,tumor growth, and metastasis by administering the compounds andpharmaceutical compositions of the present invention.

[0402] The present invention also relates to methods for treatingosteoporosis by administering the compounds and pharmaceuticalcompositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0403] The present invention relates to compounds useful as integrinreceptor antagonists. Representative compounds of the present inventionare described by the following structural formula:

[0404] wherein X is selected from the group consisting of

[0405] a 5- or 6-membered monocyclic aromatic or nonaromatic ring systemhaving 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting ofN, O, and S wherein the ring nitrogen atoms are unsubstituted orsubstituted with one R¹ substituent and the ring carbon atoms areunsubstituted or substituted with one or two R¹ substituents, and

[0406] a 9- to 14-membered polycyclic ring system, wherein one or moreof the rings is aromatic, and wherein the polycyclic ring system has 0,1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, andS, and wherein the ring nitrogen atoms are unsubstituted or substitutedwith one R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents;

[0407] Y is selected from the group consisting of

[0408] —(CH₂)_(m),

[0409] —(CH₂)_(m)—O—(CH₂)_(n)—,

[0410] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—,

[0411] —(CH₂)_(m)—S—(CH₂)_(n)—,

[0412] —(CH₂)_(m)—SO—(CH₂)_(n)—,

[0413] —(CH₂)_(m)—SO₂—(CH₂)_(n)—,

[0414] —(CH2)m—O—(CH2)n—O—(CH2)p—,

[0415] —(CH2)m—O—(CH2)n—NR⁴—(CH2)p—,

[0416] —(CH2)m—NR⁴—(CH2)n—NR⁴—(CH2)p—,

[0417] —(CH2)m—O—(CH2)n—S—(CH2)p—,

[0418] —(CH2)m—S—(CH2)n—S—(CH2)p—,

[0419] —(CH2)m—NR⁴—(CH2)n—S—(CH2)p—,

[0420] —(CH2)m—NR⁴—(CH2)n—O—(CH2)p—,

[0421] —(CH2)m—S—(CH2)n—O—(CH2)p—, and

[0422] —(CH2)m—S—(CH2)n—NR⁴—(CH2)p—,

[0423] wherein any methylene (CH₂) carbon atom in Y, other than in R⁴,can be substituted by one or two R³ substituents;

[0424] Z is selected from the group consisting of

[0425] —CH₂CH₂—, and —CH═CH—, wherein either carbon atom can besubstituted by one or two R³ substituents;

[0426] R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈ cycloheteroalkyl C₁₋₆alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino,C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(p)amino, (C₁₋₆ alkyl)_(p)aminoC₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkoxycarbonylC₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl,C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p), (C₁₋₈alkyl)_(p)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈alkyl)_(p)aminocarbonyloxy, (aryl C₁₋₈ alkyl)_(p)amino, (aryl)_(p)amino,aryl C₁₋₈ alkylsulfonylamino, and C₁₋₈ alkylsulfonylamino;

[0427] or two R¹ substituents, when on the same carbon atom, are takentogether with the carbon atom to which they are attached to form acarbonyl group;

[0428] each R³ is independently selected from the group consisting of

[0429] hydrogen,

[0430] aryl,

[0431] C₁₋₁₀ alkyl,

[0432] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0433] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0434] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0435] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0436] aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—,

[0437] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0438] halogen,

[0439] hydroxyl,

[0440] oxo,

[0441] trifluoromethyl,

[0442] C₁₋₈ alkylcarbonylamino,

[0443] aryl C₁₋₅ alkoxy,

[0444] C₁₋₅ alkoxycarbonyl,

[0445] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0446] C₁₋₆ alkylcarbonyloxy,

[0447] C₃₋₈ cycloalkyl,

[0448] (C₁₋₆ alkyl)_(p)amino,

[0449] amino C₁₋₆ alkyl,

[0450] arylaminocarbonyl,

[0451] aryl C₁₋₅ alkylaminocarbonyl,

[0452] aminocarbonyl,

[0453] aminocarbonyl C₁₋₆ alkyl,

[0454] hydroxycarbonyl,

[0455] hydroxycarbonyl C₁₋₆ alkyl,

[0456] HC≡C—(CH₂)_(t)—,

[0457] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0458] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0459] aryl-C≡C—(CH₂)_(t)—,

[0460] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0461] CH₂═CH—(CH₂)_(t)—,

[0462] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0463] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0464] aryl-CH═CH—(CH₂)_(t)—,

[0465] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0466] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0467] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0468] C₁₋₆ alkoxy,

[0469] aryl C₁₋₆ alkoxy,

[0470] aryl C₁₋₆ alkyl,

[0471] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0472] (aryl)_(p)amino,

[0473] (aryl)_(p)amino C₁₋₆ alkyl,

[0474] (aryl C₁₋₆ alkyl)_(p)amino,

[0475] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0476] arylcarbonyloxy,

[0477] aryl C₁₋₆ alkylcarbonyloxy,

[0478] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0479] C₁₋₈ alkylsulfonylamino,

[0480] arylsulfonylamino,

[0481] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0482] arylsulfonylamino C₁₋₆ alkyl,

[0483] aryl C₁₋₆ alkylsulfonylamino,

[0484] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0485] C₁₋₈ alkoxycarbonylamino,

[0486] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0487] aryloxycarbonylamino C₁₋₈ alkyl,

[0488] aryl C₁₋₈ alkoxycarbonylamino,

[0489] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0490] C₁₋₈ alkylcarbonylamino,

[0491] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0492] arylcarbonylamino C₁₋₆ alkyl,

[0493] aryl C₁₋₆ alkylcarbonylamino,

[0494] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0495] aminocarbonylamino C₁₋₆ alkyl,

[0496] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0497] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0498] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0499] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0500] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0501] aminosulfonylamino C₁₋₆ alkyl,

[0502] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0503] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0504] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0505] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0506] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0507] C₁₋₆ alkylsulfonyl,

[0508] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0509] arylsulfonyl C₁₋₆ alkyl,

[0510] aryl C₁₋₆ alkylsulfonyl,

[0511] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0512] C₁₋₆ alkylcarbonyl,

[0513] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0514] arylcarbonyl C₁₋₆ alkyl,

[0515] aryl C₁₋₆ alkylcarbonyl,

[0516] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0517] C₁₋₆ alkylthiocarbonylamino,

[0518] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0519] arylthiocarbonylamino C₁₋₆ alkyl,

[0520] aryl C₁₋₆ alkylthiocarbonylamino,

[0521] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0522] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0523] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0524] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and

[0525] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl;

[0526] or two R³ substituents, when on the same carbon atom are takentogether with the carbon atom to which they are attached to form acarbonyl group or a cyclopropyl group,

[0527] wherein any of the alkyl groups of R³ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R³is selected such that in the resultant compound the carbon atom or atomsto which R³ is attached is itself attached to no more than oneheteroatom;

[0528] each R⁴ is independently selected from the group consisting of

[0529] hydrogen,

[0530] aryl,

[0531] aminocarbonyl,

[0532] C₃₋₈ cycloalkyl,

[0533] amino C₁₋₆ alkyl,

[0534] (aryl)_(p)aminocarbonyl,

[0535] (aryl C₁₋₅ alkyl)_(p)aminocarbonyl,

[0536] hydroxycarbonyl C₁₋₆ alkyl,

[0537] C₁₋₈ alkyl,

[0538] aryl C₁₋₆ alkyl,

[0539] (C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,

[0540] (aryl C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl,

[0541] C₁₋₈ alkylsulfonyl,

[0542] C₁₋₈ alkoxycarbonyl,

[0543] aryloxycarbonyl,

[0544] aryl C₁₋₈ alkoxycarbonyl,

[0545] C₁₋₈ alkylcarbonyl,

[0546] arylcarbonyl,

[0547] aryl C₁₋₆ alkylcarbonyl,

[0548] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0549] aminosulfonyl,

[0550] C₁₋₈ alkylaminosulfonyl,

[0551] (aryl)_(p)aminosulfonyl,

[0552] (aryl C₁₋₈ alkyl)_(p)aminosulfonyl,

[0553] arylsulfonyl,

[0554] arylC1-6 alkylsulfonyl,

[0555] C₁₋₆ alkylthiocarbonyl,

[0556] arylthiocarbonyl, and

[0557] aryl C₁₋₆ alkylthiocarbonyl,

[0558] wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents;

[0559] R⁵ and R⁶ are each independently selected from the groupconsisting of

[0560] hydrogen,

[0561] C₁₋₁₀ alkyl,

[0562] aryl,

[0563] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0564] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0565] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0566] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0567] aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—,

[0568] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0569] halogen,

[0570] hydroxyl,

[0571] C₁₋₈ alkylcarbonylamino,

[0572] aryl C₁₋₅ alkoxy,

[0573] C₁₋₅ alkoxycarbonyl,

[0574] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0575] C₁₋₆ alkylcarbonyloxy,

[0576] C₃₋₈ cycloalkyl,

[0577] (C₁₋₆ alkyl)_(p)amino,

[0578] amino C₁₋₆ alkyl,

[0579] arylaminocarbonyl,

[0580] aryl C₁₋₅ alkylaminocarbonyl,

[0581] aminocarbonyl,

[0582] aminocarbonyl C₁₋₆ alkyl,

[0583] hydroxycarbonyl,

[0584] hydroxycarbonyl C₁₋₆ alkyl,

[0585] HC≡C—(CH₂)_(t)—,

[0586] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0587] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0588] aryl-C≡C—(CH₂)_(t)—,

[0589] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0590] CH₂═CH—(CH₂)_(t)—,

[0591] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0592] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0593] aryl-CH═CH—(CH₂)_(t)—,

[0594] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0595] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0596] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0597] C₁₋₆ alkoxy,

[0598] aryl C₁₋₆ alkoxy,

[0599] aryl C₁₋₆ alkyl,

[0600] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0601] (aryl)_(p)amino,

[0602] (aryl)_(p)amino C₁₋₆ alkyl,

[0603] (aryl C₁₋₆ alkyl)_(p)amino,

[0604] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0605] arylcarbonyloxy,

[0606] aryl C₁₋₆ alkylcarbonyloxy,

[0607] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0608] C₁₋₈ alkylsulfonylamino,

[0609] arylsulfonylamino,

[0610] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0611] arylsulfonylamino C₁₋₆ alkyl,

[0612] aryl C₁₋₆ alkylsulfonylamino,

[0613] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0614] C₁₋₈ alkoxycarbonylamino,

[0615] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0616] aryloxycarbonylamino C₁₋₈ alkyl,

[0617] aryl C₁₋₈ alkoxycarbonylamino,

[0618] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0619] C₁₋₈ alkylcarbonylamino,

[0620] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0621] arylcarbonylamino C₁₋₆ alkyl,

[0622] aryl C₁₋₆ alkylcarbonylamino,

[0623] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0624] aminocarbonylamino C₁₋₆ alkyl,

[0625] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0626] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0627] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0628] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0629] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0630] aminosulfonylamino C₁₋₆ alkyl,

[0631] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0632] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0633] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0634] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0635] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0636] C₁₋₆ alkylsulfonyl,

[0637] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0638] arylsulfonyl C₁₋₆ alkyl,

[0639] aryl C₁₋₆ alkylsulfonyl,

[0640] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0641] C₁₋₆ alkylcarbonyl,

[0642] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0643] arylcarbonyl C₁₋₆ alkyl,

[0644] aryl C₁₋₆ alkylcarbonyl,

[0645] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0646] C₁₋₆ alkylthiocarbonylamino,

[0647] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0648] arylthiocarbonylamino C₁₋₆ alkyl,

[0649] aryl C₁₋₆ alkylthiocarbonylamino,

[0650] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0651] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0652] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0653] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and

[0654] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl;

[0655] or R⁵ and R⁶ are taken together with the carbon atom to whichthey are attached to form a carbonyl group,

[0656] wherein any of the alkyl groups of R⁵ or R⁶ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁵ and R⁶ are selected such that in the resultantcompound the carbon atom to which R⁵ and R⁶ are attached is itselfattached to no more than one heteroatom;

[0657] R⁷ and R⁸ are each independently selected from the groupconsisting of

[0658] hydrogen,

[0659] C₁₋₁₀ alkyl,

[0660] aryl,

[0661] aryl-(CH₂)_(r)—O—(CH₂)_(s)—,

[0662] aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—,

[0663] aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,

[0664] aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,

[0665] aryl-(CH₂)_(r)—N(R⁴)—C(O )—(CH₂)_(s)—,

[0666] aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,

[0667] halogen,

[0668] hydroxyl,

[0669] C₁₋₈ alkylcarbonylamino,

[0670] aryl C₁₋₅ alkoxy,

[0671] C₁₋₅ alkoxycarbonyl,

[0672] (C₁₋₈ alkyl)_(p)aminocarbonyl,

[0673] C₁₋₆ alkylcarbonyloxy,

[0674] C₃₋₈ cycloalkyl,

[0675] (C₁₋₆ alkyl)_(p)amino,

[0676] amino C₁₋₆ alkyl,

[0677] arylaminocarbonyl,

[0678] aryl C₁₋₅ alkylaminocarbonyl,

[0679] aminocarbonyl,

[0680] aminocarbonyl C₁₋₆ alkyl,

[0681] hydroxycarbonyl,

[0682] hydroxycarbonyl C₁₋₆ alkyl,

[0683] HC≡C—(CH₂)_(t)—,

[0684] C₁₋₆ alkyl-C≡C—(CH₂)_(t)—,

[0685] C₃₋₇ cycloalkyl-C≡C—(CH₂)_(t)—,

[0686] aryl-C≡C—(CH₂)_(t)—,

[0687] C₁₋₆ alkylaryl-C≡C—(CH₂)_(t)—,

[0688] CH₂═CH—(CH₂)_(t)—,

[0689] C₁₋₆ alkyl-CH═CH—(CH₂)_(t)—,

[0690] C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,

[0691] aryl-CH═CH—(CH₂)_(t)—,

[0692] C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—,

[0693] C₁₋₆ alkyl-SO₂—(CH₂)_(t)—,

[0694] C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—,

[0695] C₁₋₆ alkoxy,

[0696] aryl C₁₋₆ alkoxy,

[0697] aryl C₁₋₆ alkyl,

[0698] (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0699] (aryl)_(p)amino,

[0700] (aryl)_(p)amino C₁₋₆ alkyl,

[0701] (aryl C₁₋₆ alkyl)_(p)amino,

[0702] (aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,

[0703] arylcarbonyloxy,

[0704] aryl C₁₋₆ alkylcarbonyloxy,

[0705] (C₁₋₆ alkyl)_(p)aminocarbonyloxy,

[0706] C₁₋₈ alkylsulfonylamino,

[0707] arylcarbonylamino,

[0708] arylsulfonylamino,

[0709] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0710] arylsulfonylamino C₁₋₆ alkyl,

[0711] aryl C₁₋₆ alkylsulfonylamino,

[0712] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0713] C₁₋₈ alkoxycarbonylamino,

[0714] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0715] aryloxycarbonylamino C₁₋₈ alkyl,

[0716] aryl C₁₋₈ alkoxycarbonylamino,

[0717] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0718] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0719] arylcarbonylamino C₁₋₆ alkyl,

[0720] aryl C₁₋₆ alkylcarbonylamino,

[0721] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0722] aminocarbonylamino C₁₋₆ alkyl,

[0723] arylaminocarbonylamino,

[0724] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0725] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0726] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0727] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0728] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0729] aminosulfonylamino C₁₋₆ alkyl,

[0730] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0731] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0732] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0733] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0734] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0735] C₁₋₆ alkylsulfonyl,

[0736] C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0737] arylsulfonyl C₁₋₆ alkyl,

[0738] aryl C₁₋₆ alkylsulfonyl,

[0739] aryl C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,

[0740] C₁₋₆ alkylcarbonyl,

[0741] C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0742] arylcarbonyl C₁₋₆ alkyl,

[0743] aryl C₁₋₆ alkylcarbonyl,

[0744] aryl C₁₋₆ alkylcarbonyl C₁₋₆ alkyl,

[0745] C₁₋₆ alkylthiocarbonylamino,

[0746] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0747] arylthiocarbonylamino C₁₋₆ alkyl,

[0748] aryl C₁₋₆ alkylthiocarbonylamino,

[0749] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0750] (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0751] (aryl)_(p)aminocarbonyl C₁₋₆ alkyl,

[0752] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl,

[0753] (aryl C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, and

[0754] C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino,

[0755] wherein any of the alkyl groups of R⁷ and R⁸ are eitherunsubstituted or substituted with one to three R¹ substituents, andprovided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom;

[0756] R⁹ is selected from the group consisting of

[0757] hydrogen,

[0758] C₁₋₈ alkyl,

[0759] aryl,

[0760] aryl C₁₋₈ alkyl,

[0761] C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

[0762] aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl,

[0763] C₁₋₈ alkylaminocarbonylmethylene, and

[0764] C₁₋₈ dialkylaminocarbonylmethylene;

[0765] wherein

[0766] each m is independently an integer from 0 to 6;

[0767] each n is independently an integer from 0 to 6;

[0768] each p is independently an integer from 0 to 2;

[0769] each r is independently an integer from 1 to 3;

[0770] each s is independently an integer from 0 to 3; and

[0771] each t is independently an integer from 0 to 3;

[0772] and the pharmaceutically acceptable salts thereof.

[0773] In the compounds of the present invention, X is preferably a6-membered monocyclic aromatic or nonaromatic ring system having 1 or 2nitrogen atoms wherein each carbon atom is either unsubstituted orsubstituted with one R¹ substituent, or

[0774] a 9- to 14-membered polycyclic ring system, wherein one or moreof the rings is aromatic, and wherein the polycyclic ring system has 0,1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, andS, and wherein the ring nitrogen atoms are unsubstituted or substitutedwith one R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents.

[0775] More preferably X is selected from the group consisting of

[0776] Most preferably X is

[0777] In the compounds of the present invention, Y is preferablyselected from the group consisting of

[0778] —(CH₂)_(m),

[0779] —(CH₂)_(m)—O—(CH₂)_(n)—,

[0780] —(CH₂)_(m)—NR⁴—(CH₂)_(n)—,

[0781] —(CH₂)_(m)—S—(CH₂)_(n)—,

[0782] —(CH₂)_(m)—SO—(CH₂)_(n)—,

[0783] —(CH₂)_(m)—SO₂—(CH₂)_(n)—,

[0784] —(CH2)m—O—(CH2)n—O—(CH2)p—,

[0785] —(CH2)m—O—(CH2)n—NR⁴—(CH2)p—, —(CH2)m—NR⁴—(CH2)n—NR⁴—(CH2)p—, and—(CH2)m—NR⁴—(CH2)n—O—(CH2)p—,

[0786] wherein any methylene (CH₂) carbon atom in Y, other than in R⁴,can be substituted by one or two R³ substituents. More preferably, Y isselected from the group consisting of

[0787] (CH₂)_(m), (CH₂)_(m)—S—(CH₂)_(n), and (CH₂)_(m)—NR⁴—(CH₂)_(n),

[0788] wherein any methylene (CH₂) carbon atom in Y, other than in R⁴,can be substituted by one or two R³ substituents.

[0789] In the compounds of the present invention, Z is preferablyselected from the group consisting of

[0790] —CH₂CH₂—, and —CH═CH—, wherein either carbon atom can besubstituted by one or two R³ substituents.

[0791] More preferably, Z is selected from the group consisting of

[0792] and —CH₂CH₂—, wherein either carbon atom can be substituted byone or two R³ substituents.

[0793] In the compounds of the present invention, R¹ and R² arepreferably selected from the group consisting of hydrogen, halogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, hydroxy, nitro,cyano, trifluoromethyl, and trifluoromethoxy.

[0794] More preferably, R¹ and R² are selected from the group consistingof hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, trifluoromethyl, andtrifluoromethoxy.

[0795] In the compounds of the present invention, R³ is preferablyselected from the group consisting of

[0796] hydrogen,

[0797] fluoro,

[0798] trifluoromethyl,

[0799] aryl,

[0800] C₁₋₈ alkyl,

[0801] arylC₁₋₆ alkyl

[0802] hydroxyl,

[0803] oxo,

[0804] arylaminocarbonyl,

[0805] aryl C₁₋₅ alkylaminocarbonyl,

[0806] aminocarbonyl, and

[0807] aminocarbonyl C₁₋₆ alkyl.

[0808] More preferably, R³ is selected from the group consisting of

[0809] fluoro,

[0810] aryl,

[0811] C₁₋₈ alkyl,

[0812] arylC₁₋₆ alkyl

[0813] hydroxyl,

[0814] oxo, and

[0815] arylaminocarbonyl.

[0816] In the compounds of the present invention, R⁴ is preferablyselected from the group consisting of

[0817] hydrogen,

[0818] aryl,

[0819] C₃₋₈ cycloalkyl,

[0820] C₁₋₈ alkyl,

[0821] C₁₋₈ alkylcarbonyl,

[0822] arylcarbonyl,

[0823] C₁₋₆ alkylsulfonyl,

[0824] arylsulfonyl,

[0825] arylC₁₋₆alkylsulfonyl,

[0826] arylC₁₋₆alkylcarbonyl,

[0827] C₁₋₈alkylaminocarbonyl,

[0828] arylC₁₋₅alkylaminocarbonyl,

[0829] arylC₁₋₈alkoxycarbonyl, and

[0830] C₁₋₈alkoxycarbonyl.

[0831] More preferably, R⁴ is selected from the group consisting ofhydrogen,

[0832] C₁₋₈ alkyl,

[0833] C₁₋₈ alkylcarbonyl,

[0834] arylcarbonyl,

[0835] arylC₁₋₆alkylcarbonyl,

[0836] C₁₋₆ alkylsulfonyl,

[0837] arylsulfonyl, and

[0838] arylC₁₋₆alkylsulfonyl.

[0839] In one embodiment of the present invention, R⁵ and R⁶ are eachindependently selected from the group consisting of

[0840] hydrogen,

[0841] aryl,

[0842] C₁₋₈ alkyl,

[0843] aryl-C≡C—(CH₂)_(t)—,

[0844] aryl C₁₋₆ alkyl,

[0845] CH₂═CH—(CH₂)_(t)—, and

[0846] HC≡C—(CH₂)_(t)—.

[0847] In a class of this embodiment of the present invention, R⁶ ishydrogen and R⁵ is selected from the group consisting of

[0848] hydrogen,

[0849] aryl,

[0850] C₁₋₈ alkyl,

[0851] aryl-C≡C—(CH₂)_(t)—,

[0852] aryl C₁₋₆ alkyl,

[0853] CH₂═CH—(CH₂)_(t)—, and

[0854] HC≡C—(CH₂)_(t)—.

[0855] In a subclass of this class of the present invention, R⁶, R⁷ andR⁸ are each hydrogen and R⁵ is selected from the group consisting of

[0856] hydrogen,

[0857] aryl,

[0858] C₁₋₈ alkyl,

[0859] aryl-C≡C—(CH₂)_(t)—,

[0860] aryl C₁₋₆ alkyl,

[0861] CH₂═CH—(CH₂)_(t)—, and

[0862] HC≡C—(CH₂)_(t)—.

[0863] In another embodiment of the present invention, R⁷ and R⁸ areeach independently selected from the group consisting of

[0864] hydrogen,

[0865] aryl,

[0866] C₁₋₈ alkylcarbonylamino,

[0867] C₁₋₈ alkylsulfonylamino,

[0868] arylcarbonylamino,

[0869] arylsulfonylamino,

[0870] C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl,

[0871] arylsulfonylamino C₁₋₆ alkyl,

[0872] aryl C₁₋₆ alkylsulfonylamino,

[0873] aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl,

[0874] C₁₋₈ alkoxycarbonylamino,

[0875] C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0876] aryloxycarbonylamino C₁₋₈ alkyl,

[0877] aryl C₁₋₈ alkoxycarbonylamino,

[0878] aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,

[0879] C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,

[0880] arylcarbonylamino C₁₋₆ alkyl,

[0881] aryl C₁₋₆ alkylcarbonylamino,

[0882] aryl C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl,

[0883] aminocarbonylamino C₁₋₆ alkyl,

[0884] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0885] (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0886] (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0887] arylaminocarbonylamino,

[0888] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0889] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl,

[0890] aminosulfonylamino C₁₋₆ alkyl,

[0891] (C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0892] (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0893] (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0894] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino,

[0895] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆ alkyl,

[0896] C₁₋₆ alkylthiocarbonylamino,

[0897] C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl,

[0898] arylthiocarbonylamino C₁₋₆ alkyl,

[0899] aryl C₁₋₆ alkylthiocarbonylamino,

[0900] aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl, and

[0901] C₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino.

[0902] In a class of this embodiment of the present invention, R⁸ ishydrogen and R⁷ is selected from the group consisting of

[0903] hydrogen,

[0904] aryl,

[0905] C₁₋₈ alkylcarbonylamino,

[0906] aryl C₁₋₆ alkylcarbonylamino,

[0907] arylcarbonylamino,

[0908] C₁₋₈ alkylsulfonylamino,

[0909] aryl C₁₋₆ alkylsulfonylamino,

[0910] arylsulfonylamino,

[0911] C₁₋₈ alkoxycarbonylamino,

[0912] aryl C₁₋₈ alkoxycarbonylamino,

[0913] arylaminocarbonylamino,

[0914] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0915] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0916] (C₁₋₈ alkyl)_(p)aminosulfonylamino, and

[0917] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino.

[0918] In a subclass of this class of the present invention, R⁵, R⁶ andR⁸ are each hydrogen and R⁷ is selected from the group consisting of

[0919] hydrogen,

[0920] aryl,

[0921] C₁₋₈ alkylcarbonylamino,

[0922] aryl C₁₋₆ alkylcarbonylamino,

[0923] arylcarbonylamino,

[0924] C₁₋₈ alkylsulfonylamino,

[0925] aryl C₁₋₆ alkylsulfonylamino,

[0926] arylsulfonylamino,

[0927] C₁₋₈ alkoxycarbonylamino,

[0928] aryl C₁₋₈ alkoxycarbonylamino,

[0929] arylaminocarbonylamino,

[0930] (C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0931] (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,

[0932] (C₁₋₈ alkyl)_(p)aminosulfonylamino, and

[0933] (aryl C₁₋₈ alkyl)_(p)aminosulfonylamino.

[0934] In the compounds of the present invention, R⁹ is preferablyselected from the group consisting of hydrogen, methyl, and ethyl.

[0935] More preferably, R⁹ is hydrogen.

[0936] In the compounds of the present invention, m is preferably aninteger from 0 to 4, more preferably from 2 to 4.

[0937] In the compounds of the present invention, n is preferably aninteger from 0 to 4, more preferably from 2 to 4.

[0938] In the compounds of the present invention, r is preferably aninteger from 1 to 2.

[0939] In the compounds of the present invention, s is preferably aninteger from 0 to 2.

[0940] In the compounds of the present invention, t is preferably aninteger from 0 to 2, more preferably from 0 to 1.

[0941] Illustrative but nonlimiting examples of compounds of the presentinvention that are useful as integrin receptor antagonists are thefollowing:

[0942]3-(5-(5,6,7,8-Tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0943]3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0944]3(S)-(5,6,7,8-Tetrahydroquinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid (trifluoroacetate);

[0945]2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[0946]3(S)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0947]3(R)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0948]3-(Quinolin-3-yl)-3-(7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoylamino)-propionicacid bis(trifluoroacetate);

[0949]3-(Quinolin-3-yl)-3-(6-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-hexanoylamino)-propionicacid;

[0950]3(S)-(3-Fluorophenyl)-3-(4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylamino)-butyrylamino)-propionicacid bis(trifluoroacetate);

[0951]3(S)-(5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-pent-4-enoicacid;

[0952]3(S)-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0953]2-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate salt;

[0954]3(S)-(Benzo[1,3]dioxol-5-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0955]3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0956]3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[0957]3(S)-(3-Fluorophenyl)-3-{3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid;

[0958]3(S)-(3-Fluorophenyl)-3-(2-{propyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino}-acetylamino)-propionicacid trifluoroacetate;

[0959]3(S)-(3-Fluorophenyl)-3-(2-{phenethyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino}-acetylamino)-propionicacid trifluoroacetate;

[0960]3(S)-(3-Fluorophenyl)-3-{3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pent-4-ynoylamino}-propionicacid;

[0961]3(S)-(3-Fluorophenyl)-3-{3(S)-(3-fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid bis(trifluoroacetate);

[0962]3(S)-(3-Fluoro-4-phenyl-phenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[0963]2(S)-(2-Thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[0964]3(S)-(3-Fluorophenyl)-3-{3-methyl-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid;

[0965]3(S)-(3-Fluorophenyl)-3-{2-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethylamino]-acetylamino}-propionicacid;

[0966]3(S)-(3-Fluorophenyl)-3{[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-ureido}-propionicacid;

[0967]2(S)-(Methanesulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[0968] 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(R orS),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;

[0969] 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(S orR),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;

[0970]3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl-propionyl)-amino]propionicacid;

[0971]3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethylsulfanyl)propionylamino]-propionicacid bis(trifluoroacetate);

[0972]3-(Quinolin-3-yl)-7-[(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;

[0973]3-(Quinolin-3-yl)-7-[acetyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;

[0974]3-(Quinolin-3-yl)-7-[methanesulfonyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;

[0975]3-[5-(2-Amino-pyrimidin-4-yl)-pentanoylamino]-3(S)-(quinolin-3-yl)-propionicacid;

[0976] 9-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;

[0977]2-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid bis(trifluoroacetate);

[0978]2(S)-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0979]2(R)-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0980]2(S)-(Benzenesulfonylamino)-10-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-decanoicacid;

[0981]2(S)-(Benzenesulfonylamino)-8-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-octanoicacid;

[0982]2(S)-(Cyclohexylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;

[0983]2(S)-(7,7-Dimethyl-2-oxo-bicyclo[2.2.1]hept-1(S)-ylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;

[0984]2(S)-(Phenylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0985]2(S)-(Cyclohexanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;

[0986]2(S)-(Butane-1-sulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;

[0987]2(S)-(3-Benzylureido)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0988]2(S)-(Benzyloxycarbonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0989]2(S)-(Phenylacetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0990]2(S)-(Acetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0991]2(S)-(Benzoylanmino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[0992]3-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[0993]3(S)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[0994]3(R)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[0995]3-(Quinolin-3-yl)-7-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]-naphthyridin-8-yl)-heptanoicacid bis(hydrochloride);

[0996]6-Oxo-3-(quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[0997]3-(N-Oxo-quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[0998]3-(Phenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;

[0999]3-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1000]3(R)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1001]3(S)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1002]3-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicai acid;

[1003]3(R)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1004]3(S)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1005]3-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1006]3(R)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1007]3(S)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1008]3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1009]3(S)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1010]3(R)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1011]3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid trifluoroacetate;

[1012]3-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1013]3(R)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1014]3(S)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1015]3-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1016]3(R)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1017]3(S)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1018]3-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1019]3(R)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1020]3(S)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1021]3-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1022]3(S)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1023]3(R)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1024]3-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;

[1025]3(R)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;

[1026]3(S)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;

[1027]3-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1028]3(R)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1029]3(S)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1030]3-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;

[1031]3(R)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;

[1032]3(S)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;

[1033]3-(6-Oxo-1,6-dihydro-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid bis-(trifluoroacetate);

[1034] and the pharmaceutically acceptable salts thereof.

[1035] Further illustrative of the present invention are the compoundsselected from the group consisting of

[1036]

[1037]3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[1038]2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[1039]3(S)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[1040]3(R)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;

[1041]2(S)-(2-Thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;

[1042] 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(R orS),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;

[1043] 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(S orR),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;

[1044]3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl-propionyl)-amino]propionicacid;

[1045]3-[5-(2-Amino-pyrimidin-4-yl)-pentanoylamino]-3(S)-(quinolin-3-yl)-propionicacid;

[1046]2-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid bis(trifluoroacetate);

[1047] and the pharmaceutically acceptable salts thereof.

[1048] Yet further illustrative are the compounds selected from thegroup consisting of

[1049]3(R)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1050]3(S)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1051]3(R)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1052]3(S)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1053]3(R)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1054]3(S)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1055]3(R)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1056]3(S)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1057]3(R)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1058]3(S)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1059]3(R)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid

[1060]3(S)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1061]3(R)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1062]3(S)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1063]3(R)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1064]3(S)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;

[1065]3(R)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1066]3(S)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1067]3(R)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1068]3(S)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1069]3(R)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;

[1070]3(S)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-²-yl)-nonanoicacid;

[1071]3(R)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;

[1072]3(S)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;

[1073] and the pharmaceutically acceptable salts thereof.

[1074] For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their pharmaceutically acceptable salts. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention which are generallyprepared by reacting the free base with a suitable organic or inorganicacid. Representative salts include the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts.

[1075] The compounds of the present invention can have chiral centersand can thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures, and individual diastereomers, with all isomericforms being included in the present invention. Therefore, where acompound is chiral, the separate enantiomers or diastereomers,substantially free of the other, are included within the scope of theinvention; further included are all mixtures of the two enantiomers.

[1076] Some of the compounds described herein contain olefinic doublebonds, and unless specified otherwise, are meant to include both E and Zgeometric isomers.

[1077] Some of the compounds described herein may exist with differentpoints of attachment of hydrogen, referred to as tautomers. Such anexample may be a ketone and its enol form, known as keto-enol tautomers.The individual tautomers as well as mixtures thereof are encompassedwithin the compounds of the present invention.

[1078] Compounds of the present invention may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent, for example, methanol or ethylacetate or a mixture thereof. The pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample, by the use of an optically active acid as a resolving agent, orby HPLC using a chiral stationary phase. Alternatively, any enantiomerof a compound of the present invention may be obtained by stereospecificsynthesis using optically pure starting materials or reagents of knownconfiguration.

[1079] Also included within the scope of the invention are polymorphsand hydrates of the compounds of the instant invention.

[1080] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

[1081] The term “therapeutically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by a researcher or clinician.

[1082] The term “integrin receptor antagonist,” as used herein, refersto a compound which binds to and antagonizes either the αvβ3 receptor,the αvβ5 receptor, or the αvβ6 receptor, or a compound which binds toand antagonizes combinations of these receptors (for example, a dualαvβ3/αvβ5 receptor antagonist).

[1083] The term “bone resorption,” as used herein, refers to the processby which osteoclasts degrade bone.

[1084] The term “alkyl” shall mean straight or branched chain alkanes ofone to ten total carbon atoms, or any number within this range (i.e.,methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

[1085] The term “alkenyl” shall mean straight or branched chain alkenesof two to ten total carbon atoms, or any number within this range.

[1086] The term “alkynyl” shall mean straight or branched chain alkynesof two to ten total carbon atoms, or any number within this range.

[1087] The term “cycloalkyl” shall mean cyclic rings of alkanes of threeto eight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

[1088] The term “cycloheteroalkyl,” as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, piperazinyl.

[1089] The term “alkoxy,” as used herein, refers to straight or branchedchain alkoxides of the number of carbon atoms specified (e.g., C₁₋₅alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).

[1090] The term “aryl,” as used herein, refers to a monocyclic orpolycyclic system comprising at least one aromatic ring, wherein themonocylic or polycyclic system contains 0, 1, 2, 3, or 4 heteroatomschosen from N, O, or S, and wherein the monocylic or polycylic system iseither unsubstituted or substituted with one or more groupsindependently selected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈cycloalkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylaminoC₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆ dialkylamino-C₁₋₈ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆alkyl, C₁₋₅ alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano,trifluoromethyl, oxo or C₁₋₅ alkylcarbonyloxy. Examples of aryl include,but are not limited to, phenyl, naphthyl, pyridyl, pyrryl, pyrazolyl,pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3)dioxolane, oxazolyl, isoxazolyl and thiazolyl, which are eitherunsubstituted or substituted with one or more groups independentlyselected from hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl,aryl C₁₋₈ alkyl, amino, amino C₁₋₈ alkyl, C₁₋₃ acylamino, C₁₋₃ acylaminoC₁₋₈ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylamino-C₁₋₈ alkyl, C₁₋₆dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxyC₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₅alkoxycarbonyl, C₁₋₃ alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl C₁₋₆alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, cyano, trifluoromethyl, oxo orC₁₋₅ alkylcarbonyloxy. Preferably, the aryl group is unsubstituted,mono-, di-, tri- or tetra-substituted with one to four of theabove-named substituents; more preferably, the aryl group isunsubstituted, mono-, di- or tri-substituted with one to three of theabove-named substituents; most preferably, the aryl group isunsubstituted, mono- or di-substituted with one to two of theabove-named substituents.

[1091] Whenever the term “alkyl” or “aryl” or either of their prefixroots appears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), itshall be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁₋₁₀)shall refer independently to the number of carbon atoms in an alkyl orcyclic alkyl moiety or to the alkyl portion of a larger substituent inwhich alkyl appears as its prefix root.

[1092] The terms “arylalkyl” and “alkylaryl” include an alkyl portionwhere alkyl is as defined above and to include an aryl portion wherearyl is as defined above. Examples of arylalkyl include, but are notlimited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl,phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl,thienylethyl, and thienylpropyl. Examples of alkylaryl include, but arenot limited to, toluene, ethylbenzene, propylbenzene, methylpyridine,ethylpyridine, propylpyridine and butylpyridine.

[1093] In the compounds of the present invention, two R¹ substituents,when on the same carbon atom, can be taken together with the carbon atomto which they are attached to form a carbonyl group.

[1094] In the compounds of the present invention, two R³ substituents,when on the same carbon atom, can be taken together with the carbon atomto which they are attached to form a carbonyl group. In such instances,the limitation, that in the resultant compound the carbon atom or atomsat which R³ is attached is itself attached to no more than oneheteroatom, does not apply. Also, two R³ substituents, when on the samecarbon atom, can be taken together with the carbon atom to which theyare attached to form a cyclopropyl group.

[1095] In the compounds of the present invention, R⁵ and R⁶ can be takentogether to form a carbonyl group. In such instances, the limitation,that in the resultant compound the carbon atom at which R⁵ and R⁶ isattached is itself attached to no more than one heteroatom, does notapply.

[1096] The term “halogen” shall include iodine, bromine, chlorine, andfluorine.

[1097] The term “oxy” means an oxygen (O) atom. The term “thio” means asulfur (S) atom. The term “oxo” means “=O”. The term “carbonyl” means“C═O.”

[1098] The term “substituted” shall be deemed to include multipledegrees of substitution by a named substitutent. Where multiplesubstituent moieties are disclosed or claimed, the substituted compoundcan be independently substituted by one or more of the disclosed orclaimed substituent moieties, singly or plurally. By independentlysubstituted, it is meant that the (two or more) substituents can be thesame or different.

[1099] Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

[1100] In choosing compounds of the present invention, one of ordinaryskill in the art will recognize that the various substituents, i.e. X,Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, and the subscripts m, n, p,r, s, and t are to be chosen in conformity with well-known principles ofchemical structure connectivity.

[1101] Representative compounds of the present invention typicallydisplay submicromolar affinity for the integrin receptors, particularlythe αvβ3, αvβ5, and/or αvβ6 receptors. Compounds of this invention aretherefore useful for treating mammals suffering from a bone conditioncaused or mediated by increased bone resorption, who are in need of suchtherapy. Pharmacologically effective amounts of the compounds, includingpharamaceutically acceptable salts thereof, are administered to themammal, to inhibit the activity of mammalian osteoclasts.

[1102] The compounds of the present invention are administered indosages effective to antagonize the αvβ3 receptor where such treatmentis needed, as, for example, in the prevention or treatment ofosteoporosis.

[1103] Further exemplifying the invention is the method wherein theintegrin receptor antagonizing effect is an αvβ3 antagonizing effect. Anillustration of the invention is the method wherein the αvβ3antagonizing effect is selected from inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, or metastasis. Preferably,the αvβ3 antagonizing effect is the inhibition of bone resorption.

[1104] An example of the invention is the method wherein the integrinreceptor antagonizing effect is an αvβ5 antagonizing effect. Morespecifically, the αvβ5 antagonizing effect is selected from inhibitionof restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, tumor growth, or metastasis.

[1105] Illustrating the invention is the method wherein the integrinreceptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect.More particularly, the dual αvβ3/αvβ5 antagonizing effect is selectedfrom inhibition of: bone resorption, restenosis, angiogenesis, diabeticretinopathy, macular degeneration, inflammation, viral disease, tumorgrowth, or metastasis.

[1106] Illustrating the invention is the method wherein the integrinreceptor antagonizing effect is an αvβ6 antagonizing effect. Moreparticularly, the αvβ6 antagonizing effect is selected from inhibitionof angiogenesis, inflammatory response, or wound healing.

[1107] Illustrating the invention is the method wherein the αvβ3antagonizing effect is selected from inhibition of bone resorption,inhibition of restenosis, inhibition of angiogenesis, inhibition ofdiabetic retinopathy, inhibition of macular degeneration, inhibition ofatherosclerosis, inflammation, viral disease, or inhibition of tumorgrowth and metastasis. Preferably, the αvβ3 antagonizing effect is theinhibition of bone resorption.

[1108] More particularly illustrating the invention is a pharmaceuticalcomposition comprising any of the compounds described above and apharmaceutically acceptable carrier. Another example of the invention isa pharmaceutical composition made by combining any of the compoundsdescribed above and a pharmaceutically acceptable carrier. Anotherillustration of the invention is a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

[1109] Further illustrating the invention is a method of treating and/orpreventing a condition mediated by antagonism of an integrin receptor ina mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds describedabove. Preferably, the condition is selected from bone resorption,osteoporosis, restenosis, diabetic retinopathy, macular degeneration,angiogenesis, atherosclerosis, inflammation, viral disease, cancer,tumor growth, and metastasis. More preferably, the condition is selectedfrom osteoporosis and cancer. Most preferably, the condition isosteoporosis.

[1110] More specifically exemplifying the invention is a method ofeliciting an integrin antagonizing effect in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above. Preferably, the integrin antagonizing effect is an αvβ3antagonizing effect; more specifically the αvβ3 antagonizing effect isselected from inhibition of bone resorption, inhibition of restenosis,inhibition of atherosclerosis, inhibition of angiogenesis, inhibition ofdiabetic retinopathy, inhibition of macular degeneration, inhibition ofinflammation, inhibition of viral disease, or inhibition of tumor growthor metastasis. Most preferably, the αvβ3 antagonizing effect isinhibition of bone resorption. Alternatively, the integrin antagonizingeffect is an αvβ5 antagonizing effect, an αvβ6 antagonizing effect, or amixed αvβ3, αvβ5, and αvβ6 antagonizing effect. Examples of αvβ5antagonizing effects are inhibition of restenosis, atherosclerosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,or tumor growth. Examples of αvβ6 antagonizing effects are inhibition ofangiogenesis, inflammatory response, and wound healing.

[1111] Additional examples of the invention are methods of inhibitingbone resorption and of treating and/or preventing osteoporosis in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions decribed above.

[1112] Additional illustrations of the invention are methods of treatinghypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

[1113] More particularly exemplifying the invention is the use of any ofthe compounds described above in the preparation of a medicament for thetreatment and/or prevention of osteoporosis in a mammal in need thereof.Still further exemplifying the invention is the use of any of thecompounds described above in the preparation of a medicament for thetreatment and/or prevention of bone resorption, tumor growth, cancer,restenosis, atherosclerosis, diabetic retinopathy, macular degeneration,inflammation, viral disease, and/or angiogenesis.

[1114] Also exemplifying the invention are compositions furthercomprising an active ingredient selected from the group consisting of

[1115] a.) an organic bisphosphonate or a pharmaceutically acceptablesalt or ester thereof,

[1116] b.) an estrogen receptor modulator,

[1117] c.) a cytotoxic/antiproliferative agent,

[1118] d.) a matrix metalloproteinase inhibitor,

[1119] e.) an inhibitor of epidermal-derived, fibroblast-derived, orplatelet-derived growth factors,

[1120] f.) an inhibitor of VEGF,

[1121] g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1,

[1122] h.) a cathepsin K inhibitor, and

[1123] i.) a prenylation inhibitor, such as a farnesyl transferaseinhibitor or a geranylgeranyl transferase inhibitor or a dualfarnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof.

[1124] (See B. Millauer et al., “Dominant-Negative Inhibition of Flk-1Suppresses the Growth of Many Tumor Types in Vivo”, Cancer Research, 56,1615-1620 (1996), which is incorporated by reference herein in itsentirety).

[1125] Preferably, the active ingredient is selected from the groupconsisting of:

[1126] a.) an organic bisphosphonate or a pharmaceutically acceptablesalt or ester thereof,

[1127] b.) an estrogen receptor modulator, and

[1128] c.) a cathepsin K inhibitor; and mixtures thereof.

[1129] Nonlimiting examples of such bisphosphonates include alendronate,etidronate, pamidronate, risedronate, ibandronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially alendronate monosodiumtrihydrate.

[1130] Nonlimiting examples of estrogen receptor modulators includeestrogen, progesterin, estradiol, droloxifene, raloxifene, andtamoxifene.

[1131] Nonlimiting examples of cytotoxic/antiproliferative agents aretaxol, vincristine, vinblastine, and doxorubicin.

[1132] Cathepsin K, formerly known as cathepsin O2, is a cysteineprotease and is described in PCT International Application PublicationNo. WO 96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issuedMar. 3, 1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all ofwhich are incorporated by reference herein in their entirety. Cysteineproteases, specifically cathepsins, are linked to a number of diseaseconditions, such as tumor metastasis, inflammation, arthritis, and boneremodeling. At acidic pH's, cathepsins can degrade type-I collagen.Cathepsin protease inhibitors can inhibit osteoclastic bone resorptionby inhibiting the degradation of collagen fibers and are thus useful inthe treatment of bone resorption diseases, such as osteoporosis.

[1133] The present invention is also directed to combinations of thecompounds of the present invention with one or more agents useful in theprevention or treatment of osteoporosis. For example, the compounds ofthe instant invention may be effectively administered in combinationwith effective amounts of other agents such as an organicbisphosphonate, an estrogen receptor modulator, or a cathepsin Kinhibitor.

[1134] Additional illustrations of the invention are methods of treatingtumor growth or metastasis in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound described above and one or more agents known to becytotoxic/antiproliferative. Also, the compounds of the presentinvention can be administered in combination with radiation therapy fortreating tumor growth and metastasis.

[1135] In addition, the integrin αvβ3 antagonist compounds of thepresent invention may be effectively administered in combination with agrowth hormone secretagogue in the therapeutic or prophylactic treatmentof disorders in calcium or phosphate metabolism and associated diseases.These diseases include conditions which can benefit from a reduction inbone resorption. A reduction in bone resorption should improve thebalance between resorption and formation, reduce bone loss or result inbone augmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions. These diseases include: osteoporosis (includingestrogen deficiency, immobilization, glucocorticoid-induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcemia, metastatic bone disease, periodontaldisease, cholelithiasis, nephrolithiasis, urolithiasis, urinarycalculus, hardening of the arteries (sclerosis), arthritis, bursitis,neuritis and tetany. Increased bone resorption can be accompanied bypathologically high calcium and phosphate concentrations in the plasma,which would be alleviated by this treatment. Similarly, the presentinvention would be useful in increasing bone mass in patients withgrowth hormone deficiency. Thus, preferred combinations are simultaneousor alternating treatments of an αvβ3 receptor antagonist of the presentinvention and a growth hormone secretagogue, optionally including athird component comprising an organic bisphosphonate, preferablyalendronate monosodium trihydrate.

[1136] In accordance with the method of the present invention, theindividual components of the combination can be administered separatelyat different times during the course of therapy or concurrently individed or single combination forms. The instant invention is thereforeto be understood as embracing all such regimes of simultaneous oralternating treatment, and the term “administering” is to be interpretedaccordingly. It will be understood that the scope of combinations of thecompounds of this invention with other agents useful for treatingintegrin-mediated conditions includes in principle any combination withany pharmaceutical composition useful for treating osteoporosis.

[1137] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[1138] The compounds of the present invention can be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, topical (e.g., ocular eyedrop),subcutaneous, intramuscular or transdermal (e.g., patch) form, all usingforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an αvβ3 antagonist.

[1139] The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician, veterinarian or clinician can readily determine and prescribethe effective amount of the drug required to prevent, counter or arrestthe progress of the condition.

[1140] Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

[1141] In the methods of the present invention, the compounds hereindescribed in detail can form the active ingredient, and are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as ‘carrier’materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

[1142] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

[1143] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[1144] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

[1145] In the schemes and examples below, various reagent symbols andabbreviations have the following meanings: AcOH: Acetic acid. BH₃·DMS:Borane · dimethylsulfide. BOC(Boc): t-Butyloxycarbonyl. BOP:Benzotriazol-1-yloxytris(dimethylamino)- phosphoniumhexafluorophosphate. CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl. CDI:Carbonyldiimidazole. CH₂Cl₂: Methylene chloride. CH₃CN AcetonitrileCHCl₃: Chloroform. DEAD: Diethyl azodicarboxylate. DIAD: Diisopropylazodicarboxylate. DIBAR or DIBAL-H: Diisobutylaluminum hydride. DIPEA:Diisopropylethylamine. DMAP: 4-Dimethylaminopyridine. DME:1,2-Dimethoxyethane. DMF: Dimethylformamide. DMSO: Dimethylsulfoxide.DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate. EDC:1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide · HCl EtOAc: Ethylacetate. EtOH: Ethanol. HOAc: Acetic acid. HOAT:1-Hydroxy-7-azabenzotriazole HOBT: 1-Hydroxybenzotriazole. IBCF:Isobutylchloroformate LDA: Lithium diisopropylamide. MeOH: Methanol.MMNG 1,1-methyl-3-nitro-1-nitrosoguanidine NEt₃: Triethylamine. NMM:N-methylmorpholine. PCA · HCl: Pyrazole carboxamidine hydrochloride.Pd/C: Palladium on activated carbon catalyst. Ph: Phenyl. PyCLU:Chloro-N,N,N′,N′-(tetramethylene)-formamidinium hexafluorophosphate.pTSA p-Toluenesulfonic acid. TEA: Triethylamine. TFA: Trifluoroaceticacid. THF: Tetrahydrofuran. TLC: Thin Layer Chromatography. TMEDA:N,N,N′,N′-Tetramethylethylenediamine. TMS: Trimethylsilyl.

[1146] The novel compounds of the present invention can be preparedaccording to the procedure of the following schemes and examples, usingappropriate materials and are further exemplified by the followingspecific examples. The compounds illustrated in the examples are not,however, to be construed as forming the only genus that is considered asthe invention. The following examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted.

[1147] The following Schemes and Examples describe procedures for makingrepresentative compounds of the present invention. Moreover, byutilizing the procedures described in detail in PCT InternationalApplication Publication Nos. WO95/32710, published Dec. 7, 1995, andWO95/17397, published Jun. 29, 1995, both of which are incorporated byreference herein in their entirety, in conjunction with the disclosurecontained herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein.Additionally, for a general review describing the synthesis ofβ-alanines which can be utilized as the C-terminus of the compounds ofthe present invention, see Cole, D. C., Recent Stereoselective SyntheticApproaces to β-Amino Acids, Tetrahedron, 1994, 50, 9517-9582; Juaristi,E, et al., Enantioselective Synthesis of β-Amino Acids, AldrichimicaActa, 1994, 27, 3. In particular, synthesis of the 3-methyl-β-alanine istaught in Duggan, M. F. et al., J. Med. Chem., 1995, 38, 3332-3341; the3-ethynyl-β-alanine is taught in Zablocki, J. A., et al., J. Med. Chem.,1995, 38, 2378-2394; the 3-(pyridin-3-yl)-β-alanine is taught in Rico,J. G. et al., J. Org. Chem., 1993, 58, 7948-7951; and the 2-amino- and2-tosylamino-β-alanines are taught in Xue, C-B, et al., Biorg. Med.Chem. Letts., 1996, 6, 339-344. The references described in thisparagraph are all also incorporated by reference herein in theirentirety.

6-Oxo-heptanoic acid methyl ester (1-2)

[1148] To a rapidly stirred mixture of diethyl ether (175 ml) and 40%KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture wasstirred for 10 minutes. The ethereal layer was transferred to a solutionof 6-oxo-heptanoic acid 1-1 (5.0 g, 34.68 mmol) and CH₂Cl₂ at 0° C. Thesolution was purged with argon for 30 minutes and then concentrated.Flash chromatography (silica, 30% to 50% EtOAc/hexanes) gave ester 1-2as a clear oil.

[1149] TLC R_(f)=0.88 (silica, EtOAc) ¹H NMR (300 MHz, CDCl₃) δ3.67 (s,3H), 2.46 (m,2H), 2.33 (m, 2H), 2.14 (s, 3H), 1.62 (m, 4H).

5-[1,8]-Naphthyridin-2-yl-pentanoic acid methyl ester (1-4)

[1150] A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3,2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J.Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absoluteethanol (23 mL) was heated at reflux for 18 h. Following evaporativeremoval of the solvent, the residue was chromatographed (silica gel, 80%ethyl acetate/hexane, then ethyl acetate) to give ester 14 as a whitesolid.

[1151] TLC R_(f)=0.38 (silica, EtOAc) ¹H NMR (300 MHz, CDCl₃) δ9.08 (m,1H), 8.16 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.45 (m, 1H), 7.39(d, J=8.3 Hz, 1H), 3.66 (s, 3H), 3.08 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.6Hz, 2H), 1.94 (m,2H), 1.78 (m, 2H).

5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-pentanoic acid methylester (1-5)

[1152] A mixture of 14 (630 mg, 2.58 mmol) and 10% Pd/carbon (95 mg) inEtOH (25 mL) was stirred under a balloon of hydrogen for 72 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70% ethyl acetate/hexanes) to give 1-5 as acolorless oil.

[1153] TLC R_(f)=0.58 (silica, ethyl acetate). ¹H NMR (300 MHz, CDCl₃)δ7.05 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.3 Hz, 1H), 4.72 (s, 1H), 3.66 (s,3H), 3.40 (m, 2H), 2.69 (t, J=6.3 Hz, 2H), 2.53 (m, 2H), 2.33 (m, 2H),1.90 (m, 2H), 1.66 (m, 4H).

5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-pentanoic acidhydrochloride (1-6)

[1154] A mixture of 1-5 (620 mg, 2.50 mmol) and 6N HCl (12 mL) washeated at 50° C. for 18 h. Evaporative removal of the solvent gave 1-6as a yellow solid.

[1155]¹H NMR (300 MHz, CD₃OD) δ7.59 (d, J=7.3 Hz, 1H), 6.63 (d, J=7.3Hz, 1H), 3.48 (m, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.35 (m, 2H),1.95 (m,2H), 1.69 (m, 4H).

3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)propionicacid ethyl ester (1-8)

[1156] A mixture of 1-6 (50 mg, 0.1847 mmol), 1-7 (49 mg, 0.1847 mmol)(Rico et al., J. Org. Chem., 1993, 58, 7948), BOP (90 mg, 0.2032 mmol)and NMM (0.122 mL, 1.11 mmol) in CH₃CN (2 mL) was stirred for 18 h. Themixture was diluted with ethyl acetate, washed with sat. NaHCO₃, brine,and dried over MgSO₄. Following evaporative removal of the solvent, theresidue was chromatographed (silica gel, 20% MeOH/ethyl acetate) to give1-8 as a yellow oil.

[1157] TLC R_(f)=0.23 (20% MeOH/ethyl acetate). ¹H NMR (300 MHz, CDCl₃)δ8.54 (s,1H), 8.43 (d, J=4.9Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.85 (m,1H), 7.39 (m, 1H), 7.15 (d, J=7.3Hz, 1H), 6.34 (d, J=7.3 Hz, 1H), 5.37(t, J=7.3 Hz, 1H), 4.05 (q, J=7.1Hz, 2H), 3.38 (t, J=5.5 Hz, 2H), 2.64(m,4H),2.52 (m, 2H), 2.22 (m, 2H), 1.86 (m, 2H), 1.64 (m, 4H), 1.16 (t,J=7. 1 Hz,3H).

3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)propionicacid (1-9)

[1158] To a solution of 1-8 (0.1847 mmol) in EtOH (2 mL) was added 1NNaOH (0.250 ml, 0.250 mmol). After stirring for 2 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 15:10:1:1ethyl acetate/EtOH/water/NH₄OH) to give 1-9 as a white solid.

[1159] TLC R_(f)=0.15 (15:10:1:1 ethyl acetate/EtOH/water/NH₄OH).

[1160]¹H NMR (300 MHz, CD₃OD) δ8.55 (s, 1H), 8.42 (d, J=4.9Hz, 1H), 7.84(d, J=8.1 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.41 (m,1H), 6.50 (d,J=7.1Hz, 1H), 5.42 (m, 1H,), 3.47 (t, J=5.6 Hz, 2H), 2.55 to 2.81 (m, 6H),2.41 (m, 1H), 2.34 (m, 1H), 2.93 (m, 2H), 1.71 (m, 4H).

Ethyl 4-(1,8-naphthyridin-2-yl)butanoate (2-3)

[1161] Aminoaldehyde 1-3 (2.02 g, 16.6 mmol, prepared according to Het.1993, 36, 2513), ketone 2-2 (5.3 mL, 33.1 mmol) and L-proline (0.48 g,4.17 mmol) were combined in 75 mL EtOH. After heating at refluxovernight, the reaction was concentrated. Flash chromatography (silica,EtOAc) provided 2-3 as an off-white crystalline solid.

[1162] TLC R_(f) 0.23 (silica, EtOAc) ¹H NMR (300 MHz, CDCl₃): δ9.09(dd, J=4, 2Hz, 1H), 8.17 (dd, J=8, 2Hz, 1H), 8.12 (d, J=8Hz, 1H), 7.46(dd, J=8, 4Hz, 1H), 7.42 (d, J=8Hz, 1H), 4.12 (q, J=7Hz, 2H), 3.11 (t,J=8Hz, 2H), 2.44 (t, J=7Hz, 1H), 2.26 (qn, J=8Hz, 2H), 1.25 (t, J=7Hz,3H).

Ethyl 4-(1,2,3,4-tetrahydro-1,8-naphthyidin-7-yl)butanoate (2-4)

[1163] A solution of 2-3 (2.3 g, 9.4 mmol) in 50 mL EtOAc was treatedwith 10% Pd/C (230 mg) and a hydrogen balloon. After 4 days the reactionfiltered through celite, concentrated, and purified by flashchromatography (silica, 70% EtOAc/hexane), providing 2-4 as a yellowOil.

[1164] TLC R_(f) 0.40 (silica, EtOAc) ¹H NMR (300 MHz, CDCl₃): δ7.05 (d,J=7Hz, 1H), 6.35 (d, J=7Hz, 1H), 4.73 (br s, 1H), 4.12 (q, J=7Hz, 2H),2.69 (t, J=6Hz, 2H), 2.57 (t, J=8Hz, 2H), 2.33 (t, J=7Hz, 2H), 1.98 (m,2H), 1.90 (m, 2H), 1.25 (t, J=7Hz, 3H).

4-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)butanoic acid hydrochloride(2-5)

[1165] Ester 2-4 (1.8 g, 7.25 mmol) in 36 mL 6 N HCl was heated at 50°C. for 4 h, then concentrated, providing 2-5 as a yellow solid. ¹H NMR(300 MHz, CD₃OD): δ7.59 (d, J=7Hz, 1H), 6.63 (d, J=7Hz, 1H), 3.50 (t,J=5Hz, 2H), 2.82 (t, J=6Hz, 2H), 2.74 (t, J=8Hz, 2H), 2.38 (t, J=7Hz,2H), 2.02-1.90 (m, 4H).

2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid ethyl ester ditrifluoroacetate salt (3-2)

[1166] A solution of5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoic acidhydrochloride (1-6) (304 mg, 0.85 mmol) in DMF (5 mL) was treatedsuccessively with HOBT (115 mg, 0.85 mmol), the amine 3-1 (prepared in asimilar fashion as intermediate A-4 but substituting benzenesulfonylchloride in place of 4-iodo-benzenesulfonyl chloride) (263 mg, 0.85mmol), EDC (195 mg, 1.02 mmol) and triethylamine (0.24 mL, 1.71 mmol).The resulting solution was stirred at room temperature for 18 hr., thenpoured into saturated NaHCO₃ and extracted twice with EtOAc. Mterwashing with brine, the solvent was evaporated and the residuechromatographed (silica gel; 5% MeOH in CHCl₃) to give an oil. Furtherpurification using reverse phase HPLC afforded the title compound as awhite solid.

[1167] FAB mass spectrum, found (M+H)⁺=489.3

2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate salt (3-3)

[1168] To a solution of the ester 3-2 (180 mg, 0.37 mmol) in methanol (2mL) and water (2 mL) was added 1N LiOH (0.74 mL, 0.74 mmol) and themixture was stirred for 4 hr. After this time, 1N HCl (1 mL) was added,and the solution was purified by reverse phase HPLC to provide the titlecompound as a white solid.

[1169] FAB mass spectrum, found (M+H)⁺=461.21

2(S)-(2-Thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate salt (4-2)

[1170] A solution of5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoic acidhydrochloride 1-6 (0.164 mg, 0.7 mmol) in DMF (5 mL) was treatedsuccessively with HOBT (104 mg, 0.77 mmol), the amine 4-1 (Egbertson, etal. Bioorg Med Chem. Letts., 1996, 6, 2519; 211 mg, 0.85 mmol), EDC (161mg, 0.84 mmol) and N-methylmorpholine (0.23 mL, 2.1 mmol). The resultingsolution was stirred at room temperature for 18 hr., then poured intosaturated NaHCO₃ and extracted twice with EtOAc. After washing withbrine, the solvent was evaporated and the residue was used withoutfurther purification in the next step. To a solution of this ester (290mg, 0.6 mmol) in 20 mL of THF, methanol and water (1:1:1) was addedLiOH.H₂O (100 mg, 2.4 mmol) and the mixture was stirred for 20 hr. Afterthis time, the THF and methanol were removed in vacuo and the aqueoussolution was purified by reverse phase HPLC to provide the titlecompound as a white solid.

[1171]¹H NMR (CD₃OD) δ7.73-7.78 (1H, dd), 7.54-7.62 (2H, m), 7.08-7.15(1H, m), 6.60-6.67 (1H, d), 4.08-4.16 (1H, m), 3.57-3.67 (1H, dd),3.40-3.50 (2H, t), 3.20-3.30 (1H, m), 2.75-2.85 (2H, t), 2.65-2.75 (2H,t), 2.20-2.30 (2H, t), 1.85-1.97 (2H, m), 1.60-1.80 (4H, m).

3-Amino-3-(quinolin-3-yl)-propionic acid (5-2)

[1172] A solution containing quinoline-3-carboxaldehyde 5-1 (5 g, 31.8mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g,63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 h.After cooling to room temperature, the resulting white solid wascollected by filtration and washed with cold ethanol (150 mL) and thendried under vacuum to provide 5-2 as a white solid (3.84 g, 17.8 mmol,56%).

[1173]¹H NMR (300 MHz, D₂O): δ8.91 (d, J=2 Hz 1H), 8.21 (d, J=2 Hz, 1H),8.12 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz, 1H), 7.72 (t, J=7 Hz, 1H), 7.54(t, J=7 Hz, 1,H), 4.72 (m, 1H), 2.73 (m, 2H).

3-Phenylacetylamino-3-(quinolin-3-yl)-propionic (5-3)

[1174] A 0° solution of 5-2 (3.5 g, 16.2 mmol) and NaHCO₃ (2.7 g, 32.4mmol) in 50% aqueous dioxane (100 mL) was treated dropwise with asolution of phenylacetyl chloride (3.00 g, 19.4 mmol) in 25 mL ofdioxane. The resulting solution was stirred at 0° for 2.5 h then warmedto room temperature, diluted with H₂O (50 mL) and washed with ether(2×100 mL). The aqueous layer was adjusted to pH=3 with 3N HCl and thenextracted with CH₂Cl₂ (3×150 mL). The pooled organic extracts weredried, filtered and concentrated to afford 5-3 as an off white solid.

[1175]¹H NMR (300 MHz, CD₃OD): δ8.85 (d, J=2 Hz 1H), 8.20 (d, J=2 Hz,1H), 8.00 (d, J=8 Hz, 1H), 7.86 (d, J=7 Hz, 1H), 7.76 (t, J=7 Hz, 1H),7.52 (t, J=7 Hz, 1,H), 7.28 (m, 6H), 5.53 (t, J=6.8 Hz, 1H), 3.57 (s,2H), 2. 96 (m, 2H).

3-Amino-3(S)-(quinolin-3-yl)-propionic acid dihydrochloride (5-6)

[1176] Acid 5-3 (5.0 g, 15 mmol) was suspended in water (3.5 L) thentreated with 1N NaOH (15 mL) to afford a clear solution. Penicillinamidase (Sigma, EC 3.5.1.11, 10,000 U) in 0.1 M phosphate buffer wasadded. The pH of the mixture was adjusted to 7.8 with 1N NaOH and thesolution was stirred at room temperature for 4 days. The reaction wasmonitored periodically by HPLC and the reaction stopped once the 50%conversion was reached. Next, the reaction solution was cooled to 0° C.and adjusted to pH=3 with 3N HCl. An oily yellow precipitate formed andwas collected by filtration then washed with water to afford crude 5-5(1.8 g, 5.3 mmol). The filtrate was extracted with CH₂Cl₂ (3×500 mL) toafford additional 5-5 contaminated by phenylacetic acid. Both batches ofcrude 5-5 were combined and stirred in 3 N HCl (200 mL) at 50° for 12 hthen cooled, washed with ether (2×100 mL) and evaporated to afford 5-6.3-Amino-3-(quinolin-3-yl)-propionic acid ethyl ester dihydrochloride(5-7)

[1177] The resolved acid 5-6 was converted to 5-7 by refluxing inethanolic HCl.

[1178]¹H NMR (300 MHz, CD₃OD): δ9.25 (d, J=2 Hz 1H), 8.31 (d, J=2 Hz,1H), 8.15 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz, 1H), 7.72 (t, J=7 Hz, 1H),7.54 (t, J=7 Hz, 1,H), 4.72 (m, 1H), 4.15 (q, J=6 Hz, 2H), 2.73 (m, 2H)1.18 (t, J=6 Hz, 3H).

Ethyl3-(5-(5,6,7,8-tetrahydro-[1,8]-naphthydin-2-yl)pentanoylamino)-3(S)-(quinolin-3-yl)-propionate(5-8)

[1179] A mixture of 1-6 (200 mg, 0.74 mmol), 5-7 (202 mg, 0.74 mmol),NMM (366 mL, 3.33 mmol), HOBT (130 mg, 0.96 mmol) and EDC (184 mg, 0.96mmol) in 2 mL DMF was stirred overnight. After diluting with EtOAc (100mL), the mixture was washed with sat. NaHCO₃, water, and brine, dried(MgSO₄), filtered and concentrated, and chromatographed on silica (10%EtOH/EtOAc) providing 5-8 as a colorless glass.

[1180] TLC R_(f)=0.6 (10% EtOH/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ8.80 (d,J=2 Hz 1H), 8.31 (d, J=2 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz,1H), 7.72 (t, J=7 Hz, 1H), 7.54 (t, J=7 Hz, 1,H), 7.00 (d, J=8.1 Hz,1H), 6.53 (d, J=7.5 Hz, 1H), 5.34 (m, 1H), 4.06 (q, J=7,5 Hz, 2H),3.48(t, J=5.7 Hz, 2H), 2.79 (m, 4H), 2.63 (m, 2H), 2.25 (m, 2H), 1.94 (m,2H), 1.64 (m, 4H) 1.12 (t, J=7,5 Hz, 3H).

3(S)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)pentanoylamino)-propionicacid (5-9)

[1181] Ester 5-8 (145 mg, 0.320 mmol) was dissolved in 1 mL EtOH andtreated with 1N LiOH (352 mL, 0.35 mmol) and stirred at room temperatureovernight. The reaction solution was neutralized with 1N HCl (352 mL),evaporated, and purified by chromatography on silica gel (60% 20:1:1EtOH/NH₄OH/H₂O—40% EtOAc) to afford 5-9 as a white solid.

[1182] TLC R_(f)=0.5 (60% 20:1:1 EtOH/NH₄OH/H₂O—40% EtOAc) ¹H NMR (300MHz, CD₃OD) δ8.80 (d, J=2 Hz 1H), 8.31 (d, J=2 Hz, 1H), 8.15 (d, J=8 Hz,1H), 7.84 (d, J=7 Hz, 1H), 7.72 (t, J=7 Hz, 1H), 7.54 (t, J=7 Hz, 1,H),7.00 (d, J=8.1 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 5.34 (m, 1H), 3.48 (t,J=5.7 Hz, 2H), 2.79 (m, 4H), 2.63 (m, 2H), 2.25 (m, 2H), 1.94 (m, 2H),1.64 (m, 4H).

3(S)-(5,6,7,8-Tetrahydro-quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate (5-10)

[1183] A mixture of 5-8 (0.1 g, 0.3 mmol) and PtO₂ (0.04 g) in 10 mL TFAwas purged with argon 3 times under vacuum, and treated under balloonhydrogenation condition for 18 hr. It was then filtered through a celitepad. The solution was concentrated. EtOH (3 mL) and LiOH (1 mL, 1 M, 1mmol) were added. After stirring for 3 hr, the reaction mixture wastreated with 2N HCl (2 mL), concentrated and purified by reverse phaseHPLC (C18 column; gradient: H₂O/CH₃CN/TFA from 95:5:0.1 to 5:95:0.1 over45 min) to give the desired product 5-10 as the TFA salt.

[1184]¹H NMR (300 MHz, CD₃OD) δ8.50 (s, 1H), 8.23 (s, 1H), 7.52 (d, 1H),6.54 (d, 1H), 5.33 (t, 1H), 3.50 (t, 2H), 3.08 (t, 2H), 2.94 (m, 4H),2.80 (t, 2H), 2.68 (t. 2H), 2.28 (m, 2H), 1.96 (m, 6H), 1.66 (m, 4H).

1-Bromo-3-(2,2-diethoxy-ethoxy)-benzene (6-2)

[1185] To a suspension of NaH (2.77 g, 115.6 mmol) in DMF (100 mL) at 0°C. was added a solution of 3-bromophenol 6-1 in DMF (40 mL) over 40 min.After the addition was complete, the solution was stirred for anadditional 30 min. The solution was then treated with neatbromoacetaldehyde diethyl acetal (17.36 g, 115.6 mmol). The solution washeated at 100° C. for 8 h, cooled to room temperature, and extractedwith Et₂O (3×200 mL). The combined organic extracts were washed with 10%aq. NaOH (100 mL) and brine (100 mL), dried over MgSO₄, filtered andconcentrated to give 6-2 as a yellow oil.

[1186] TLC R_(f)=0.4 (10% ethyl acetate/hexanes). ¹H NMR (300 MHz,CHCl₃) δ7.19-7.05 (m, 3H), 6.85 (d, 1H), 4.81 (t, 1H, J=6.8 Hz), 3.99(d, 2H, J=6.8 Hz), 3.71 (m, 4H), 1.22 (t, 6H, J=7.1 Hz) ppm.

6-Bromo-benzofuran (6-3)

[1187] To a solution of the acetal 6-2 in toluene (200 mL) was addedpolyphosphoric acid (20 g). The biphasic mixture was heated to 100° C.and stirred at this temperature for 4 h. The mixture was cooled to roomtemperature, poured onto ice, and extracted with Et₂O (2×200 mL). Thecombined organic extracts were washed with saturated aq. NaHCO₃ andbrine. The solution was dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (100% hexanes) to givethe product 6-3 as a yellow oil.

[1188] TLC R_(f)=0.3 (100% hexanes). ¹H NMR (300 MHz, CHCl₃) δ7.68 (s,1H), 7.60 (d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36 (dd, 1H,J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9 Hz) ppm.

3-(Benzofuran-6-yl)-acrylic acid ethyl ester (6-4)

[1189] A mixture of the 6-bromo-benzofuran 6-3 (1.74 g, 8.79 mmol),ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)₂ (0.099 g, 0.44 mmol),tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g,43.9 mmol) in DMF (10 mL) was heated to 100° C. in a sealed tube for 4h. The mixture was cooled to room temperature, diluted with water, andextracted with Et₂O (2×40 mL). The combined organic extracts were washedwith brine (30 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography (10% ethyl acetate/hexanes)to give the ester 6-4 as an off-white solid.

[1190] TLC R_(f)=0.3 (10% ethyl acetate/hexanes). ¹H NMR (300 MHz,CHCl₃) δ7.78 (d, 1H, J=15.9 Hz), 7.68 (d, 1H, J=2.4 Hz), 7.66 (s, 1H),7.59 (d, 1H, J=8.4 Hz), 7.43 (dd, 1H, J=9.0, 1.5 Hz), 6.78 (m, 1H), 6.47(d, 1H, J=15.9 Hz), 4.27 (q, 2H, J=7.2 Hz), 1.34 (t, 3H, J=7.2 Hz) ppm.

3(S)-(Benzofuran-6-yl)-3-[benzyl-(1(R)-phenyl-ethyl)-amino]-propionicacid ethyl ester (6-5)

[1191] A solution of N-benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5M soln in hexanes). The resulting solution was stirred at 0° C. for 30min and then cooled to −78° C. A solution of acrylate 6-4 (0.681 g, 3.15mmol) in THF (5 mL) was added. After stirring for 15 min at −78° C.,satd. aq. NH₄Cl soln (5 mL) was added and the cold bath removed. Themixture was warmed to room temperature, and extracted with Et₂O (2×40mL). The combined organic extracts were washed with brine (30 mL), driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (10% ethyl acetate/hexanes) to give theβ-aminoester 6-5 as a yellow oil.

[1192] TLC R_(f)=0.8 (10% ethanol/dichloromethane). ¹H NMR (300 MHz,CHCl₃) δ7.58 (m, 3H), 7.41 (m, 2H), 7.22 (m, 9H), 7.59 (s, 1H), 4.58 (m,1H), 4.05 (m, 1H), 3.91 (q, 2H, J=7.1 Hz), 3.72 (m, 2H), 2.62 (m, 2H),1.21 (d, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.1 Hz) ppm.

3(S)-Amino-3-(2,3-dihydro-benzofuran-6-yl)-propionic acid ethyl ester(6-6)

[1193] A mixture of the dibenzylamine 6-5 (1.19 g, 2.78 mmol) inEtOH/H₂O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treatedwith Pd(OH)₂ (1.19 g). The mixture was placed under 1 atm of H₂. Afterstirring for 18 h, the mixture was diluted with EtOAc, and filteredthrough celite. The filtrate was concentrated and the residue purifiedby flash chromatography (10% ethyl acetate/dichloromethane) to give theester 6-6 as a white solid.

[1194] TLC R_(f)=0.25 (10% ethanol/dichloromethane). ¹H NMR (300 MHz,CD₃OD) as the trifluoroacetate salt: δ7.25 (d, 1H, J=8.1 Hz), 6.88 (m,1H), 7.66 (s, 1H), 6.82 (s, 1H), 4.58 (m, 3H), 4.12 (m, 2H), 3.30 (m,1H), 3.19 (m, 2H), 2.98 (m, 2H), 1.11 (t, 3H, J=7.2 Hz) ppm.

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid (6-7)

[1195] A solution of the amine 6-6 (0.162 g, 0.596 mmol), acid 1-6(0.183 g, 0.775 mmol), EDC (0.148 g, 0.775 mmol), NMM (0.156 g, 1.55mmol), and HOAT (0.105 g, 0.775 mmol) in DMF (6 mL) was stirred at roomtemperature for 12 h. The solution was concentrated and the residuepurified by preparative HPLC (gradient conditions: 95:05 to 50:50H₂O/MeCN with 0.1% TFA) to give the ester (0.227 g) as a yellow oil. Theester was dissolved in a solution of EtOH/H₂O (6 mL of a 9:1 mixture)and treated with LiOH (0.065 g, 1.55 mmol). After stirring for 3 h, thesolution was concentrated to a paste which was purfied by preparativeHPLC (gradient conditions: 95:05 to 50:50 H₂O/MeCN with 0.1% HCl) togive 6-7 as a white solid.

[1196] TLC R_(f)=0.24 (5% MeOH/CH₂Cl₂). ¹H NMR (300 MHz, CD₃OD) δ7.57(d, J=7.2 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.79 (dd, J=1.5, 7.2 Hz, 1H),6.70 (s, 1H), 6.58 (d, J=7.2 Hz, 1H), 5.27 (t, J=8.4 Hz, 1H), 4.50 (t,J=8.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.14 (t, J=8.7 Hz, 2H), 2.81 (t,J=6.0 Hz, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 2.26 (m, 2H), 1.94 (m, 2H),1.64 (m, 4H) ppm.

3-(3-Hydroxy-4-nitro-phenyl)-acrylic acid ethyl ester (7-2)

[1197] To a solution of aldehyde 7-1 (15.0 g, 98.0 mmol) in CH₂Cl₂ (300mL) was slowly added carboethoxymethylenetriphenylphosphorane (34.1 g,98.0 mmol). The orange solution was stirred for 12 h at ambienttemperature. The solution was concentrated to a paste and purified byflash chromatography (10% EtOAc/CH₂Cl₂) to give 7-2 as a yellow solid.

[1198] TLC R_(f)=0.51 (30% ethyl acetate/hexanes). ¹H NMR (300 MHz,CD₃OD) δ8.08 (d, J=8.4 Hz, 1H), 7.63 (d, J=16.2 Hz, 1H), 7.35 (d, J=1.5Hz, 1H), 7.27 (dd, J=8.4, 1.5 Hz, 1H), 6.65 (d, J=15.9 Hz, 1H), 4.25 (q,J=7.2 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H) ppm.

3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-acrylic acid ethyl ester (7-3)

[1199] To a solution of the nitrophenol 7-2 (12.0 g, 57.4 mmol) in warm(70° C.) AcOH/H₂O (200 mL) was added iron dust (9.61 g, 172.2 mmol). Thebrown heterogeneous mixture was stirred for 30 min at 70-80° C. Themixture was filtered hot through celite, and the celite bed washed withEtOAc (2×200 mL). The filtrate was cautiously neutralized with satd. aq.NaHCO₃ (3×100 mL). The solution was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (5% MeOHin CH₂Cl₂) to give an orange solid (9.6 g, 81%). A portion of this solid(4.5 g, 21.7 mmol) was dissolved in THF (150 mL) and treated with1,1-carbonyldiimidazole (3.87 g, 23.8 mmol), and the solution wasstirred at ambient temperature for 24 h. The solution was diluted withEtOAc (100 mL) and washed with 10% HCl (50 mL) and brine (50 mL). Thesolution was dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography (5% MeOH in CH₂Cl₂) to give 7-3 asa yellow solid.

[1200] TLC R_(f)=0.49 (5% MeOH/CH₂Cl₂). ¹H NMR (300 MHz, CD₃OD) δ7.77(d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.1Hz, 1H), 6.47 (d, J=15.9 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2Hz, 3H) ppm.

3(S)-Amino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid ethylester (7-4)

[1201] A solution of N-benzyl-α-(R)-methylbenzylamine (4.08 g, 19.3mmol) in THF (120 mL) at 0° C. was treated with n-BuLi (7.72 mL of a 2.5M soln in hexanes). The resulting solution was stirred at 0° C. for 30min and then cooled to −78° C. A solution of acrylate 7-3 (1.5 g, 6.43mmol) in THF (20 mL) was added. After stirring for 15 min at −78° C.,satd. aq. NH₄Cl soln (25 mL) was added and the cold bath removed. Themixture was warmed to room temperature, and extracted with Et₂O (2×40mL). The combined organic extracts were washed with brine (30 mL), driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (30% ethyl acetate/hexanes) to give 2.74 g of theβ-aminoester as a yellow oil. The aminoester was dissolved inEtOH/H₂O/AcOH (54 mL/4.8 mL/1.2 mL), degassed with argon, and treatedwith Pd(OH)₂ (2.74 g). The mixture was placed under 1 atm of H₂. Afterstirring for 18 h, the mixture was diluted with EtOAc and filteredthrough celite. The filtrate was concentrated to give 7-4 as anoff-white solid.

[1202] TLC R_(f)=0.10 (5% MeOH/CH₂Cl₂). ¹H NMR (300 MHz, CD₃OD) δ7.34(s, 1H), 7.26 (dd, J=1.2, 8.1 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.65 (t,J=7.2 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 2.98 (m, 2H), 1.20 (t, J=7.2 Hz,3H) ppm.

3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propiomcacid trifluoroacetate (7-5)

[1203] A solution of the amine 74 (0.196 g, 0.784 mmol), acid 1-6 (0.222g, 0.941 mmol), EDC (0.189 g, 0.988 mmol), NMM (0.190 g, 1.88 mmol), andHOAT (0.134 g, 0.988 mmol) in DMF (6 mL) was stirred at room temperaturefor 12 h. The solution was concentrated and the residue purified bypreparative HPLC (gradient conditions: 95:05 to 50:50 H₂O/MeCN with 0.1%TFA) to give the ester (0.144 g) as a yellow oil. The ester wasdissolved in a solution of EtOH/H₂O (6 mL of a 9:1 mixture) and treatedwith LiOH (0.065 g, 1.55 mmol). After stirring for 3 h, the solution wasconcentrated to a paste which was purified by preparative HPLC (gradientconditions: 95:05 to 50:50 H₂O/MeCN with 0.1% TFA) to give 0.068 g (14%for two steps) of acid 7-5 as a white solid.

[1204] TLC R_(f)=0.11 (5% MeOH/CH₂Cl₂). ¹H NMR (300 MHz, CD₃OD) δ7.54(d, J=8.7 Hz, 1H), 7.19 (s, 1H), 7.16 (d, J=8.4, 1H), 7.00 (d, J=8.1 Hz,1H), 6.53 (d, J=7.5 Hz, 1H), 5.34 (t, J=6.9 Hz, 1H), 3.48 (t, J=5.7 Hz,2H), 2.79 (m, 4H), 2.63 (m, 2H), 2.25 (m, 2H), 1.94 (m, 2H), 1.64 (m,4H) ppm.

2-Dimethoxymethyl-[1,8]naphthyridine (8-1)

[1205] A mixture containing 1-3 (30 g, 0.245 mol), pyruvaldehydedimethylacetal (87 g, 0.737 mol), and L-proline (7.0g, 0.062 mol) inMeOH (300 mL) was refluxed under argon for 16 h. The cooled solution wasfiltered, evaporated and the residue dissolved in CH₂Cl₂ (500 mL) andwashed with water and brine then dried and concentrated to a volume ofca. 100 mL. Hexane (300 mL) was added and the mixture was kept at 0° C.for 3 h, then filtered affording 8-1 as an off-white crystalline solid.¹H NMR (300 MHz, CDCl₃) δ, 9.14 (d, J=2.2 Hz, 1H); 8.26 (d, J=8.7 Hz,1H); 8.21 (dd, J=8.7, 2.2 Hz, 1H); 7.8 (d, J=8.3 Hz, 1H); 7.5 (m, 1H);5.48 (s, 1H); 3.53 (s, 6H).

2-Dimethoxymethyl-5,6,7,8-tetrahydro-[1,8]naphthyridine (8-2)

[1206] A solution of 8-1 (10 g, 0.049 mol) in ethanol (100 ml) wastreated with 10% Pd on C (1.5 g) and the resulting mixture stirred undera H₂ filled balloon for 12.5 h. The catalyst was removed by filtrationthrough celite and the solution concentrated to afford 8-2 as a yellowcrystalline solid.

[1207]¹H NMR (300 MHz, CDCl₃) δ7.18 (d, J=7.12 Hz, 1H); 6.71 (d, J=7.12Hz, 1H); 5.18 (s, 1H); 4.96 (br, s, 1H); 3.43 (s, 6H); 3.4 (m, 2H); 2.65(m, 2H); 1.91 (m, 2H).

5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (8-3)

[1208] 8-2 (10 g, 0.048 mol) was treated with trifluoroacetic acid (50mL) and the resulting solution stirred under argon for 12.5 h. The TFAwas removed at reduced pressure and the residue partitioned between sat.NaHCO₃ and CH₂Cl₂. The organic layer was dried, concentrated and passedthrough a 3 in. pad of silica gel (10% acetone/CH₂Cl₂) and concentratedto afford 8-3 as a yellow crystalline solid.

[1209]¹H NMR (300 MHz, CDCl₃) δ9.80 (s, 1H); 7.31 (d, J=7.32 Hz, 1H);7.16 (d, J=7.32 Hz, 1H); 5.31 (br, s, 1H); 3.48 (m, 2H); 2.81 (m, 2H);1.94 (m, 2H).

3(S)-Fluorophenyl-β-alanine ethyl ester hydrochloride (9-1)

[1210] The title compound 9-1 was prepared from 3-fluoro-benzaldehyde asdescribed for preparing 74 from 7-1.

[1211]¹H NMR (CD₃OD) δ1.21 (3H, t), 3.0-3.2 (2H, m), 4.16 (2H, q), 4,76(1H, t), 7.2-7.35 (3H, m), 7.5 (1H, m).

3(S)-(3-Fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionicacid ethyl ester (9-2)

[1212] To a stirred solution of (300 mg, 1.85 mmol), 9-1 (458 mg, 1.85mmol) in dichloroethane (10 ml) at 0° C. was added sodiumtriacetoxyborohydride (570 mg, 2.59 mmol). After 1 hour, the reactionwas diluted with EtOAc and then washed with 10% K₂CO₃, brine, and driedover MgSO₄. Following evaporative removal of the solvent, the residuewas chromatographed (silica gel, 5% [10:1:1 ethanol/NH₄OH/H₂O]: as ayellow solid.

[1213] TLC R_(f)=0.50 (silica, 5% [10:1:1 ethanol/NH₄OH/H₂O]: 95%[70:25:5 chloroform/ethyl acetate/methanol]) ¹H NMR (300 MHz, CDCl₃)δ7.26 (m,1H), 7.07 (m, 3H), 6.95 (m, 1H), 6.37 (d, J=7.1 Hz, 1H), 4.76(bs, 1H), 4.10 (m, 3H), 3.47 (d, J=7.1 Hz, 2H), 3.38 (m, 2H), 2.68 (m,4H), 1.90 (m, 2H), 1.18 (t, J=7.1 Hz, 3H).

3(S)-(3-Fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionicacid (9-3)

[1214] To a solution of ester 9-2 (450 mg, 1.26 mmol) in EtOH (3 mL) wasadded 1N NaOH (1.39 ml, 1.39 mmol). After stirring for 1 h, the solventswere evaporated and the residue was dissolved in 1N HCl (1.39 ml, 1.39mmol). The solution was concentrated and then azeotroped with CH₃CN togive the acid 9-3 as a brown solid.

[1215]¹H NMR (300 MHz, CD₃OD) δ7.45 (m,1H), 7.10 to 7.28 (m, 4H), 6.36(d, J=7.3 Hz, 1H), 4.41 (m, 1H), 3.80 (s, 2H), 3.31 (m, 2H), 2.62 to2.85 (m, 4H), 1.90 (m, 2H).

3(S)-(3-Fluorophenyl)-3-{3(S)-(3-fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid ethyl ester (9-4)

[1216] A mixture of acid 9-3 (235 mg, 0.6056 mmol), amine 9-1 (150 mg,0.6056 mmol), BOP (350 mg, 0.7873 mmol) and NMM (0.333 mL, 3.03 mmol) inCH₃CN (5 mL) was stirred for 20 h. The mixture was diluted with ethylacetate, washed with 10% K₂CO₃, brine, and dried over MgSO₄. Evaporativeremoval of the solvent gave 9-4 as a brown oil.

[1217] TLC R_(f)=0.15 (75:10:15 chloroform/ethyl acetate/MeOH). ¹H NMR(300 MHz, CDCl₃) δ6.85 to 7.28 (m, 9H), 6.34 (d, J=7.3 Hz, 1H), 5.40 (m,1H), 4.92 (s, 1H), 4.10 (m,3H), 3.52 (d,J=5.4 Hz, 2H), 3.38 (m, 2H,),2.48 to 2.84 (m, 7H), 1.26 (t, J=7.1 Hz, 3H).

3(S)-(3-Fluorophenyl)-3-{3(S)-(3-fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid bis(trifluoroacetate) (9-5)

[1218] To a solution of 9-4 (0.6056 mmol) in EtOH (3 mL) was added 1NNaOH (1.21 ml, 1.21 mmol). After stirring for 1 h, the solvents wereevaporated and the residue was purified by Preparative HPLC (WatersDelta Pak C18: 100:0:0.1 to 5:95:0.1 H₂O/CH₃CN/TFA) to give 9-5 as awhite solid.

[1219]¹H NMR (300 MHz, CD₃OD) δ7.45 (d, J=6.8 Hz, 1H), 7.38(d, J=6.1 Hz,1H), 7.29 (m, 1H), 6.94 to 7.18 (m, 6H), 6.51 (d, J=7.6 Hz, 1H), 5.43(m,1H), 4.26 (m, 1H,), 3.81 (m, 2H), 3.49 (m, 2H), 2.69 to 2.90 (m, 4H),1.92 (m, 2H).

(3-Oxo-butyl)-carbamic acid tert-butyl ester (10-4)

[1220] A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g,105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. Thereaction was diluted with EtOAc, washed with H₂O, 10% KHSO₄(aq.), sat.NaHCO₃, dried (MgSO₄) and concentrated to give crude[2-(methoxymethyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3as a yellow oil. TLC R_(f)=0.42 (silica, 20% EtOAc/hexanes). To asolution of this crude amide in THF (500 mL) at 0° C. was added CH₃MgBr(100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10%KHSO₄(aq.) was added, the mixture warmed to 25° C., and diluted withEtOAc. The organics were washed with sat. NaHCO₃, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4as a yellow oil.

[1221] TLC R_(f)=0.35 (silica, 20% EtOAc/hexanes). ¹H NMR (300 MHz,CDCl₃) δ5.02 (br s, 1H), 3.32 (q, 2H, J=6.8 Hz), 2.66 (q, 2H, J=6Hz),2.16 (s, 3H), 1.43 (s, 9H).

(2-[1,8]Naphthyridin-2-yl-ethyl)-carbamic acid tert-butyl ester (10-5)

[1222] A solution of 104 (10 g, 53.4 mmol), 2-amino-3-formylpyridine 13(7.2 g, 64 mmol), 20% aq. KOH (1 mL), and ethanol (200 mL) was heated atreflux for 3 h. Evaporation of the solvents and flash chromatography(silica, 70 CHCl₃/28 EtOAc/2 MeOH) gave 10-5 as a solid.

[1223] TLC R_(f)=0.29 (silica, 70 CHCl₃/28 EtOAc/2 MeOH). ¹H NMR (300MHz, CDCl₃) δ9.11 (m, 1H), 8.16 (m, 2H), 7.45 (m, 2H), 5.27 (s, 1H),3.75 (m, 2H), 3.27 (m, 2H), 1.40 (s, 9H).

[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-carbamic acidtert-butyl ester (10-6)

[1224] A mixture of 10-5 (5.0 g, 20.4 mmol), 10% Pd/C (2.5 g), and EtOH(200 mL) was stirred under a balloon of hydrogen for 15 h. The mixturewas filtered, and the filtrate concentrated to give 10-6 as a yellowoil.

[1225] TLC R_(f)=0.29 (silica, 70 CHCl₃/25 EtOAc/5 MeOH). ¹H NMR (300MHz, CDCl₃) δ7.16 (d, 1H, J=6.8 Hz), 6.48 (d, 1H, J=4.9 Hz), 5.12 (br s,2H), 3.45 (m, 4H), 2.72 (m, 4H), 1.88 (m, 2H), 1.43 (s, 9H).

2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethylamine dihydrochloride(10-7)

[1226] Through a solution of 10-6 (4.0 g, 16 mmol) in EtOAc (200 mL) at0° C. was bubbled a stream of HCl gas for 10 minutes. After anadditional 30 minutes, the mixture was purged with argon for 1 h andthen concentrated. The residue was dissolved in acetonitrile andconcentrated to give 10-7 as a yellow solid.

[1227]¹H NMR (300 MHz, CD₃OD) δ7.62 (d, 1H, J=7 Hz), 6.70 (d, 1H, J=7Hz), 3.53 (t, 2H, J=6 Hz), 3.34 (m, 2H), 3.11 (m, 2H), 2.84 (m, 2H),1.96 (m, 2H).

[tert-Butoxycarbonyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino]-aceticacid ethyl ester (10-8)

[1228] To a solution of 10-7 (2.0 g, 7.8 mmol) andN,N-diisopropylethylamine (6.8 mL) in acetonitrile (50 mL) at 0° C. wasadded ethyl bromoacetate (0.975 mL, 8.6 mmol). The mixture was stirredat 50° C. for 15 h, then cooled to 25° C. and BOC₂O (1.7 g, 7.8 mmol)was added. After 1 h, the mixture was diluted with ethyl acetate, washedwith sat. NaHCO₃, brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, 50-60% EtOAc/hexanes) gave 10-8 as a colorlessoil.

[1229] TLC R_(f)=0.5 (silica, EtOAc). ¹H NMR (300 MHz, CDCl₃) mixture ofrotamers: δ7.04 (d, 2H, J=7Hz), 6.35 (dd, 1H, J=7Hz), 4.73 (br s, 1H),4.16 (m, 2H), 3.89 (s, 1H), 3.82 (s, 1H), 3.56 (m, 2H), 3.39 (m, 2H),2.76 (m, 4H), 1.90 (m, 2H), 1.44 (m, 9H), 1.25 (m, 3H).

3-(2-[tert-Butoxycarbonyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino]-acetylamino)-3(S)-(3-fluorophenyl)-propionicacid ethyl ester (10-10)

[1230] To a solution of 10-8 (0.8 g (2.20 mmol) in EtOH (10 mL) wasadded 1N NaOH (2.4 mL, 2.4 mmol) and the mixture stirred for 1 h. Thesolvents were evaporated, and the residue was dissolved in 1N HCl,evaporated, and additionally evaporated from acetonitrile to give crude[tert-butoxycarbonyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino]-aceticacid 10-9 (0.820 g, 95%). To a mixture of the crude 10-9 in acetonitrile(2 mL) was added 3-amino-3-(S)[3-fluorophenyl]propionic acid (9-1) (0.1g, 0.404 mmol), EDC (93 mg, 1.2 eq), HOBT (55 mg, 1 eq), and NMM (0.222mL, 5 eq). After stirring for 12 h, the mixture was diluted with ethylacetate, washed with water, sat. NaHCO₃, brine, dried (MgSO₄) andconcentrated to give 10-10 as a yellow oil.

[1231] TLC R_(f)=0.18 (silica, 70: CHCl₃/25: EtOAc/5: MeOH). ¹H NMR (300MHz, CDCl₃) mixture of rotamers: δ9.52 (m, 0.5 H), 9.07 (m, 0.5 H),7.38-6.91 (m, 6H), 6.36 (m, 1H), 5.48 (m, 1H), 4.67 (m, 1H), 4.10 (m,3H), 3.82 (m, 1H), 3.66 (m, 1H), 3.44 (m, 1H), 3.21 (m, 1H), 2.82 (m,1H), 2.63 (m, 1H), 1.78 (m, 4H), 1.51-1.13 (m, 12H).

3(S)-(3-Fluorophenyl)-3-{2-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethylamino]-acetylamino}-propionicacid (10-11)

[1232] To a solution of 10-10 (0.23 g (0.404 mmol) in EtOH (2 mL) wasadded 1N NaOH (0.6 mL, 0.6 mmol) and the mixture stirred for 1 h. Thesolvents were evaporated, and the residue was dissolved indichloromethane (2 mL), and TFA (2 mL) added. After 1 h, the solutionwas concentrated from toluene. Flash chromatography (silica, 20:10:1:1to 10:10:1:1 EtOAc/EtOH/NH₄OH/H₂O) gave 10-11 as a white solid.

[1233] TLC R_(f)=0.21 (silica, 10:10:1:1 EtOAc/EtOH/NH₄OH/H₂O). ¹H NMR(300 MHz, CD₃OD): δ7.28 (m, 1H), 7.13 (m, 3H), 6.91 (m, 1H), 6.38 (d,1H, J=7Hz), 5.37 (m, 1H), 3.36 (m, 4H), 2.82 (m, 2H), 2.68 (m, 4H), 2.61(m, 2H), 1.87 (m, 2H).

[3-(N-Methoxy-N-methyl-carbamoyl)-propyl]carbamic acid tert-butyl ester(11-3)

[1234] A mixture of 11-1 (10 g, 49.2 mmol), 11-2 (4.8 mg, 49.2 mmol),EDC (9.40 g, 49.2 mmol), HOBT (6.6 g, 49.2 mmol) and NMM (2.7 mL, 246mmol) in CH₃CN (200 mL) was stirred for 20 h. The reaction wasconcentrated. The residue was dissolved in ethyl acetate, washed withH₂O, 10% KHSO₄, sat. NaHCO₃, brine, and dried over MgSO₄. Evaporativeremoval of the solvent gave 11-3 as a colorless oil.

[1235] TLC R_(f)=0.15 (50% ethyl acetate/hexanes). ¹H NMR (300 MHz,CDCl₃) δ4.96 (bs,1H), 3.55 (s, 3H), 3.46 (m, 5H), 2.48 (t, J=7.3 Hz,2H), 1.83 (m, 2H), 1.46 (s, 9H).

(4-Oxo-pentyl)carbamic acid tert-butyl ester (11-4)

[1236] To a stirred solution of 11-3 (10.0 g, 40.5 mmol) and THF (200ml)at 0° C. was added methylmagnesium bromide (27.0 ml, 91.0 mmol; 3M inether) dropwise over 20 minutes. After 2.0 hours, 10% KHSO₄ was addedslowly. The mixture was extracted with EtOAc. The organic portion waswashed with sat. NaHCO₃, brine, and dried over MgSO₄. Evaporativeremoval of the solvent gave 11-4 as a colorless oil.

[1237] TLC R_(f)=0.53 (silica, 40% EtOAc/hexanes) ¹H NMR (300 MHz,CDCl₃) δ4.62 (bs,1H), 3.13 (m, 2H), 2.49 (t, J=7.1 Hz, 2H), 2.16 (s,3H), 1.78 (m, 2H), 1.44 (s, 9H).

(3-[1,8]Naphthyridin-2-yl)-N-Boc-propylamine (11-6)

[1238] A mixture of 114 (5.0 g, 24.8 mmol), 1-3,2-amino-3-formylpyridine (3.6 g, 29.8 mmol) and 20% KOH (1 ml) inabsolute ethanol (100 mL) was heated at reflux for 8 h. Followingevaporative removal of the solvent, the residue was chromatographed(silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 11-6 asa yellow oil.

[1239] TLC R_(f)=0.40 (silica, 70:20:10 chloroform/ethylacetate/methanol) ¹H NMR (300 MHz, CDCl₃) δ9.08 (m, 1H), 8.16 (d, J=8.1Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.41 (m, 2H), 4.82 (bs, 1H), 3.21 (m,2H), 3.06 (m, 2H), 2.12 (m,2H), 1.43 (s, 9H).

3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-N-Boc-propylamine (11-7)

[1240] A mixture of 11-6 (4.0 g, 13.9 mmol) and 10% Pd/carbon (4.0 g) inEtOH (100 mL) was stirred under a balloon of hydrogen for 4 h. Followingfiltration and evaporative removal of the solvent, the residue waschromatographed (silica gel, 70:28:2 chloroform/ethyl acetate /methanol)to give 11-7 as a white solid.

[1241] TLC R_(f)=0.30 (silica, 70:25:5 chloroform/ethylacetate/methanol) ¹H NMR (300 MHz, CDCl₃) δ7.05 (d, J=7.3 Hz, 1H), 6.34(d, J=7.3 Hz, 1H), 5.48 (s, 1H), 4.79 (s, 1H), 3.37 (m, 2H), 3.15 (m,2H), 2.69 (t, J=6.3 Hz, 2H), 2.59 (t, J=7.3 Hz, 2H), 1.88 (m, 4H), 1.44(s, 9H).

3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propylaminedihydrochloride (11-8)

[1242] HCl gas was rapidly bubbled through a solution of 11-7 (2.5 g,8.6 mmol) in EtOAc (100 ml) at 0° C. for 10 minutes. After 30 minutes,the solution was purged with argon for 30 minutes. The solution wasconcentrated and then azeotroped with CH₃CN to give the amine 11-8 as ayellow solid.

[1243]¹H NMR (300 MHz, CD₃OD) δ7.61 (d, J=7.3 Hz, 1H), 6.67 (d, J=7.3Hz, 1H), 3.52 (t, J=5.6 Hz, 2H), 2.99 (m, 2H), 2.83 (m, 4H), 2.08 (m,2H),1.96 (m, 2H).

3(S)-(3-Fluorophenyl)-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-ureido}-propionicacid ethyl ester (11-9)

[1244] To a stirred solution of 9-1 (100 mg, 0.4037 mmol), DIPEA (0.380ml, 2.42 mmol) and CHCl₃ (5 ml) was added triphosgene (42 mg, 0.1413mmol). After 30 minutes, 11-8 was added. After 1 hour, the reaction wasdiluted with EtOAc and then washed with sat NaHCO₃, brine, and driedover MgSO₄. Evaporative removal of the solvent gave 11-9 as a yellowsolid.

[1245] TLC R_(f)=0.37 (silica, 75:10:15 chloroform/ethylacetate/methanol) ¹H NMR (300 MHz, CDCl₃) δ7.22 (m,2H), 7.11 (m, 2H),6.99 (m, 1H), 6.36 (d, J=7.1 Hz, 1H), 6.00 (m, 1H), 5.78 (m, 1H), 5.27(m, 1H), 4.08 (m, 2H), 3.66 (m, 1H), 3.44 (m, 2H), 3.21 (m, 2H), 2.63 to2.91 (m, 6H), 1.92 (m, 2H), 1.85 (m, 2H), 1.18 (t, J=7.1 Hz,3H).

3(S)-(3-Fluorophenyl)-3-{[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-ureido}-propionicacid (11-10)

[1246] To a solution of 11-9 (0.4037 mmol) in EtOH (3 mL) was added 1NNaOH (0.600 ml, 0.600 mmol). After stirring for 2 h, the solvents wereevaporated and the residue was chromatographed (silica gel, 20:10:1:1 to10:10:1:1 ethyl acetate/EtOH/water/NH₄OH) to give 11-10 as a whitesolid.

[1247] TLC Rf=0.21 (10:10:1:1 ethyl acetate/EtOH/water/NH₄OH). ¹H NMR(300 MHz, CD₃OD) δ7.41 (d, J=7.3 Hz, 1H), 7.31 (m, 1H), 7.17 (d, J=7.5Hz, 1H), 7.09 (d, J=10.2 Hz, 1H), 6.95 (m,1H), 6.49 (d,J=7.3 Hz, 1H),5.23 (m, 1H,), 3.45 (t, J=5.6 Hz, 2H), 3.04 (m, 1H), 2.46 to 2.79 (m,7H), 1.76 to 1.96 (m,4H).

3-(5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid (12-2)

[1248] A mixture of acid 1-6 (10.8 mg, 0.04 mmol), EDC (7.7 mg, 0.04mmol), HOBT (5.4 mg, 0.04 mmol) and NMM (0.026 mL, 0.24 mmol) in DMF (1mL) was agitated until clear solution. After 30 minutes, amine 12-1 wasadded. The solution was agitated for one minute and then let stand for18 h. The solution was diluted with ethyl acetate, washed with sat.NaHCO₃ and H₂O. Following evaporative removal of the solvent, theresidue was dissolved in 90:10 TFA/H₂O (1 ml). After 2 h, the solventswere evaporated to give acid 12-2.

[1249] TLC Rf=0.49 (silica, 10:10:1:1 ethyl acetate/EtOH/NH₄OH/H₂O).Mass calculated for C₁₆H₂₃N₃O₃=305, found M+1=306

10-Oxo-undecanoic methyl ester (13-2)

[1250] To a suspension of CuCN (5.0 g, 56 mmol) in THF (200 mL) at −78°C. was added MeMgBr (17.4 mL, 3M solution in THF) dropwise. Afteraddition was complete, the reaction mixture was warmed to −15° C. for 5min, recooled to −78° C. and then treated dropwise with 13-1 (9.3 mL, 42mmol). The reaction mixture was then warmed to −10° C. for 1.5 h andthen quenched with 90% sat. NH₄Cl (300 mL) and EtOAc (400 mL). Theorganic phase was washed with sat. NH₄Cl, sat. NaHCO₃, and brine, dried(MgSO₄), and concentrated to furnish 13-2 as a pale yellow oil.

[1251] TLC Rf=0.52 (silica, 30% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ3.65 (s, 3H), 2.43 (t, J=7 Hz, 2H), 2.30 (t, J=7 Hz, 2H), 2.13 (s, 3H),1.60 (m, 4H), 1.29 (m, 8H).

9-([1,8]Naphthyridin-2-yl)-nonanoic acid methyl ester (13-3)

[1252] A mixture of 13-2 (9.2 g, 43 mmol), 1-3 (5.3 g, 43 mmol), proline(2.5 g, 22 mmol), and ethanol (215 mL) was heated to reflux for 20 h.The cooled reaction mixture was concentrated and the residue purified byflash chromatography (silica, EtOAc) to give 13-3 as a yellow oil.

[1253] TLC Rf=0.37 (silica, EtOAc); ¹H NMR (300 MHz, CDCl₃) δ9.08 (m,1H), 8.16 (m, 1H), 8.10 (d, J=8 Hz, 1H), 7.44 (m, 1H), 7.40 (d, J=8 Hz,1H), 3.68 (s, 3H), 3.04 (m, 2H), 2.30 (m, 2H;, 1.90 (m, 2H), 1.60 (m,2H), 1.50-1.20 (m, 8H).

9-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid methyl ester(13-4)

[1254] A mixture of 13-3 (8.5 g, 28 mmol), 10% Pd/C (1.7 g), and ethanol(140 mL) was stirred under a hydrogen atmosphere for 20 h. The reactionmixture was then filtered through a celite pad and concentrated to give134 as a pale yellow oil.

[1255] TLC Rf=0.45 (silica, EtOAc); ¹H NMR (300 MHz, CDCl₃) δ7.06 (d,J=8 Hz, 1H), 6.33 (d, J=8 Hz, 1H), 3.68 (s, 3H), 3.40 (m, 2H), 2.70 (m,2H), 2.53 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.50-1.20(m, 8H).

9-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (13-5)

[1256] A solution of 134 (8.2 g, 27 mmol), 1N NaOH (30 mL), and methanol(134 mL) was stirred at 0° C. for 72 h. The methanol was evaporated andthe residue dissolved in H₂O (30 mL) and neutralized with 1N HCl toeffect a white precipitate. The solid was collected by filtration anddried at 50° C. to give 13-5.

[1257] TLC Rf=0.53 (silica, 20:1:1 ethanol/NH₄OH/H₂O); ¹H NMR (300 MHz,CD₃OD) δ7.36 (d, J=8 Hz, 1H), 6.46 (d, J=8 Hz, 1H), 3.44 (m, 2H), 2.75(m, 2H), 2.60 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.62 (m, 4H),1.40-1.30 (m, 8H).

9-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-nonanoyl[(−)-4-benzyl-2-oxazolidinone (13-6)

[1258] To a suspension of 13-5 (5.6 g, 19 mmol), THF (97 mL), and NEt₃(3.2 mL, 23 mmol) at −78° C. was added trimethylacetyl chloride (2.6 mL,21 mmol) dropwise. After addition was complete, the reaction mixture waswarmed to 0° C. for 2 h then recooled to −78° C. and treated withlithium (S)-(−)-4-benzyl-2-oxazolidinone (18 mL, 29 mmol; 1.6M solutionin THF). The reaction mixture was then warmed to 0° C. for 1 h andpoured into EtOAc (300 mL) and sat. NaHCO₃ (30 mL). The organic phasewas washed with sat. NaHCO₃, H₂O, and brine, dried (MgSO₄), andconcentrated. Flash chromatography (silica, EtOAc) gave 13-6 as an oil.

[1259] TLC Rf=0.31 (silica, EtOAc); ¹H NMR (300 MHz, CDCl₃) δ7.40-7.15(m, 5H), 7.03 (d, J=8 Hz, 1H), 6.33 (d, J=8 Hz, 1H), 4.67 (m, 1H), 4.13(m, 2H), 3.40 (m, 2H), 3.29 (1H), 3.00-2.73 (m, 3H), 2.68 (m, 2H), 2.53(m, 2H), 1.90 (m, 2H), 1.63 (m, 4H), 1.40-1.30 (m, 8H).

2-Azido-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoyl amide(13-7)

[1260] To a solution of 13-6 (19.4 mmol) and THF (65 mL) at −78° C. wasadded KHMDS (89 mL, 44.6 mmol; 0.5 M solution in THF). After 30 min.,trisyl azide (9.0 g, 29 mmol) in THF (50 mL) was added via cannula.After 3 min., the reaction was quenched with AcOH (6.9 mL) dropwisefollowed by removal of the cooling bath. After 20 h, the reactionmixture was poured into EtOAc (300 mL) and sat. NaHCO₃ (60 mL). Theorganic phase was washed with sat. NaHCO₃, H₂O, and brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 5-20%isopropanol/EtOAc) gave 13-7 as an oil.

[1261] TLC Rf=0.47 (silica, 5% NH₃ sat. ethanol/EtOAc); ¹H NMR (300 MHz,CDCl₃) δ7.03 (d, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H), 6.30 (bs, 1H), 5.77(bs, 1H), 4.82 (bs, 1H), 3.97 (m, 1H), 3.40 (m, 2H), 2.68 (m, 2H), 2.50(m, 2H), 2.00-1.20 (m, 14H).

2-Amino-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoyl amide(13-8)

[1262] A mixture of 13-7 (0.4 g, 1.2 mmol), ethanol (6 mL), and 10% Pd/C(0.4 g) was stirred under a hydrogen atmosphere for 30 min. The reactionmixture was then filtered through a celite pad and concentrated to give13-8 as an oil.

[1263] TLC Rf=0.82 (silica, 10:1:1 ethanol/NH₄OH/H₂O); ¹H NMR (300 MHz,CDCl₃) δ7.10 (m, 1H), 7.08 (d, J=8 Hz, 1H), 6.35 (d, J=8 Hz, 1H), 6.30(bs, 1H), 5.48 (bs, 1H), 5.13 (bs, 1H), 3.40 (m, 4H), 2.70 (m, 2H), 2.53(m, 2H), 2.00-1.20 (m, 14H).

2-Amino-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid(13-9)

[1264] A solution of 13-8 (0.3 g, 1.0 mmol) and 6N HCl (10 mL) washeated at 50° C. for 20 h. The reaction was then treated with conc. HCl(1 mL) and heated for an additional 5 h. The reaction mixture was thenconcentrated, the residue dissolved in H₂O and neutralized with conc.NH₄OH to form a precipitate. Filtration followed by drying under vacuumat 40° C. gave 13-9 as a gray solid.

[1265] TLC Rf=0.90 (silica, 10:1:1 ethanol/NH₄OH/H₂O); ¹H NMR (300 MHz,D₂O) δ7.00 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 3.10 (m, 2H), 3.00 (m,1H), 2.45 (m, 2H), 2.27 (m, 2H), 1.63 (m, 2H), 1.30 (m, 4H), 1.05 (m,8H).

2(S)-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (13-10)

[1266] A solution of 13-9 (0.27 g, 0.88 mmol) in H₂O/dioxane (2:1, 4.4mL) was cooled to 0° C. and then treated dropwise with 1N NaOH toattained a pH of 10.5. The reaction mixture was then treated with withPhSO₂Cl (0.23 g, 1.3 mmol) in dioxane (750 μL) while maintaining a pH of10.5 by adding 1N NaOH. After 15 min, the pH was adjusted to 7 with 1NHCl to effect a white precipitate. The precipitate was collected byfiltration and triturated with EtOAc and then ether to give 13-10 as acolorless solid.

[1267]¹H NMR (300 MHz, D₂O) δ7.50 (m, 2H), 7.10 (m, 3H), 6.95 (d, J=8Hz, 1H), 6.20 (d, J=8 Hz, 1H), 4.60 (m, 1H), 3.04 (m, 2H), 2.40 (m, 2H),2.23 (m, 2H), 1.63 (m, 2H), 1.20 (m, 4H), 0.08 (m, 8H).

3-(6,7,8,9-tetrahydro-benzo[b]-[1,8]naphthyridin-8-yl)-propionic acidethyl ester (14-2)

[1268] A solution of 2-amino-pyridine-3-carbaldehyde (1-3)(0.244 g, 2.0mmol) and 3-(3-oxo-cyclohexyl)-propionic acid ethyl ester (14-1) (0.245g, 2.00 mmol; for prep., see J. R. Wiseman et.al., J. Am. Chem. Soc.,1970, 92, 956-962) in ethanol (10 mL) was treated with L-proline (0.230g, 2.00 mmol) and heated at reflux for 12 h. The solution was cooled toambient temperature and concentrated. The residue was purified by flashchromatography (10% acetone in CH₂Cl₂) to give 14-2.

[1269]¹H NMR (300 MHz, CDCl₃) δ9.02-9.00 (m, 1H), 8.09-8.06 (m, 1H),7.84-7.37 (m, 1H), 7.27(s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.43-3.35 (m,1H), 3.31-2.98 (m, 4H), 2.84-2.75 (dd, J=11, 16 Hz, 1H), 2.47 (t, J=7.8Hz, 2H), 2.10-1.77 (m, 3H), 1.57-1.51 (m, 1H), 1.27 (t, J=7.2 Hz, 3H)ppm.

3-(1,2,3,4,6,7,8,9-octahydro-benzo[b]-[1,8]naphthyridin-8-yl)-propionicacid ethyl ester (14-3)

[1270] A mixture of 14-2 (0.298 g, 1.05 mmol) and Pd on carbon (0.060 g)in ethanol (10 mL) was placed under 1 atm of H₂ and stirred for 12 h.The solution was concentrated. The residue was purified by flashchromatography (5% MeOH in CH₂Cl₂) to give 14-3.

[1271]¹H NMR (300 MHz, CDCl₃) δ6.88 (s, 1H),4.70 (s, 1H),4.13 (q, J=7.2Hz, 2H), 3.37 (m, 2H), 2.80-2.58 (m, 5 H), 2.42-2.27 (m, 3H), 1.93-1.65(m, 6H), 1.25 (t, J=7.2 Hz, 3H) ppm.

3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionicacid (14-4)

[1272] A solution of 14-3 (0.180 g, 0.62 mmol) and NaOH (1.24 mL of a 1Nsoln, 1.24 mmol) in THF/H₂O (5 mL/5 mL) was stirred at room temperaturefor 12 h. The solution was concentrated. The residue was triturated withEt₂O to give 14-4.

[1273]¹H NMR (300 MHz, CD₃OD) δ6.91 (s, 1H), 2.75-2.58 (m, 6H),2.29-2.15 (m, 5H), 1.96-1.62 (m, 5H), 1.34-1.27 (m, 1H) ppm.

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino)-propionicacid ethyl ester (14-5)

[1274] A solution of 14-4 (0.110 g, 0.39 mmol), β-aminoester 6-6 (0.106g 0.39 mmol), EDC (0.075 g, 0.39 mmol), HOBT (0.053 g, 0.39 mmol) andN-methylmorpholine (0.164 mL, 1.17 mmol) in degassed DMF (5 mL) wasstirred at room temperature for 12 h. The solution was concentrated. Theresidue was purified by flash chromatography to give 14-5.

[1275]¹H NMR (300 MHz, CD₃OD) δ7.19 (s, 1H), 7.12-7.07 (m, 1H),6.79-6.76 (m, 1H), 6.69 (br s, 1H), 5.49-5.26 (m, 1H), 4.52-4.45 (m,2H), 4.05 (q, J=7.0 Hz, 2H), 3.41-3.38 (m, 2H), 3.15-3.10 (t, J=8.5 Hz,2H), 2.78-2.68 (m, 3H), 3.59 (m, 2H), 2.37-2.21 (m, 5H), 1.61-1.70 (m,5H), 1.38 (m, 1H), 1.18-1.14 (t, J=7.0 Hz, 3H) ppm.

3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino)-propionicacid (14-6)

[1276] A solution of 14-5 (0.050 g, 0.105 mmol) and aqueous 1N NaOH(0.210 mL, 0.210 mmol) was stirred at room temperature for 3 h. Thesolution was concentrated. The residue was triturated with Et₂O and thewhite solid collected by to give 14-6.

[1277]¹H NMR (300 MHz, CD₃OD) δ7.41 (s, 1H), 7.12-7.10 (d, J=7.3 Hz,1H), 6.80-6.78 (d, J=7.3 Hz, 1H), 6.70 (s, 1H), 5.38 (m, 1H), 4.43 (m,2H), 3.43 (m, 4H), 3.17 (m, 2H), 2.78 (m, 3H), 2.61 (m, 2H), 2.36 (m,3H), 1.95 (m, 2H), 1.77 (m, 4H), 1.40 (m, 1H) ppm.

2-Oxo-6-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-hexyl-phosphonicacid dimethyl ester (15-1)

[1278] A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) inanhydrous THF (165 mL) was cooled to −78° and treated dropwise with 2.5M n-BuLi (42.3 mL). After stirring at −78° for 45 min, a solution ofester 1-5 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and theresulting solution stirred for 30 min −78°, quenched with sat. NH₄Cl(100 mL), then extracted with ethyl acetate (3×150 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and concentrated toafford a yellow oil. Chromatography on silica gel (5% MeOH/CH₂Cl₂)afforded 15-1 as a yellow oil.

[1279] R_(f) (Silica, 5% MeOH/CH₂Cl₂)=0.20. ¹H NMR (300 MHz, CDCl₃)δ7.05 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.32 Hz, 1H), 4.80 (br, s, 1H), 3.81(s, 3H), 3.75 (s, 3H), 3.4 (m, 2H), 3.08 (d, J=22.7 Hz), 2.7-2.5 (m, 6H), 1.91 (m, 2H), 1.68 (m, 4H).

3-(Quinolin-3-yl)-7-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-(E)-hept-1-en-3-one(15-3)

[1280] Ketophosphonate 15-1 (2.0 g, 5.9 mmol), anhydrous LiCl (250 mg,5.9 mmol), and 3-quinoline-carboxaldehyde 5-1(0.77 g, 4.9 mmol) inanhydrous acetonitrile (60 mL) were treated with DBU (0.73 mL, 5.88mmol) and the resulting suspension stirred at room temperature for 1 h.The solvent was removed at reduced pressure and the resulting residuepartitioned between brine and methylene chloride. The organic layer wasremoved, dried, and concentrated to afford a yellow solid which wasrecrystallized from ethyl acetate/hexanes to afford 15-3 as an off-whitesolid.

[1281] R_(f) (Silica, 5% MeOH/CH₂Cl₂)=0.45. ¹H NMR (300 MHz, CDCl₃)δ9.05 (d, J=1.8 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 8.05(d, J=8.5 Hz, 1H),7.87 (d, J=7.5 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.68 (d, J=16 Hz, 1H),7.58 (t, J=7.5 Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 6.95 (d, J=16 Hz, 1H),6.34 (d, J=7.32 Hz, 1H), 4.80 (br, s, 1H), 3.4 (m, 2H), 2.7-2.5 (m, 6H), 1.91 (m, 2H), 1.68 (m, 4H).

3-(Quinolin-3-yl)-7-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-(E)-hept-1-en-3-ol(15-4)

[1282] A solution of 15-3 (1.33 g, 3.58 mmol) in anhydrous THF (150 mL)was cooled to −78°, then treated dropwise with i-Bu₂AlH (10.75 mL, 10.75mmol). The resulting solution was stirred at −78° for 20 min., thenquenched with ethyl acetate (20 mL), warmed to room temperature, treatedwith 1 M potassium sodium tartrate (25 mL) and stirred for 4 h. Themixture was extracted with ethyl acetate (2×150 mL) dried, filtered andevaporated to afford 15-4 as an off-white solid.

[1283] R_(f) (Silica, 10% MeOH/CH₂Cl₂)=0.10. ¹H NMR (300 MHz, CDCl₃)δ9.05 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H),7.87 (d, J=7.5 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H),7.05 (d, J=7.3 Hz, 1H), 6.86 (d, J=16 Hz, 1H), 6.45 (dd, J=16,6.5 Hz,1H) 6.37 (d, J=7.32 Hz, 1H), 4.80 (br, s, 1H), 4.4 (m, 1H) 3.4 (m,2H),2.75 (m, 2 H), 2.62 (m, 2H), 1.91 (m, 2H), 1.72 (m, 4H) 1.55(m, 2H).

3-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-(E)-non-4-enoicacid ethyl ester (15-5)

[1284] A solution of the allylic alcohol 15-4 (1.4 g, 3.75 mmol) intriethyl orthoacetate (64 mL) was treated with propionic acid (0.014 mL,0.19 mmol) and refluxed for 1.5 h. The cooled mixture was treated with asolution of 1:1 sat. brine/1N HCl (50 mL), then extracted with CH₂Cl₂(3×125 mL). The pooled organic extracts were washed with sat. NaHCO₃,dried, filtered and evaporated. Chromatography on silica gel (5%MeOH/CH₂Cl₂) afforded 15-5 as a yellow glass.

[1285] R_(f) (Silica, 5% MeOH/CH₂Cl₂)=0.25. ¹H NMR (300 MHz, CDCl₃)δ9.08 (br, s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.96(d, J=1.8 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.54(t, J-7.5 Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 6.25 (d, J=7.32 Hz, 1H), 5.6(m, 2H), 4.05 (m, 2H), 4.05 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2 H), 2.65(m, 2H),2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45(m,2 H), 1.08 (t, J=7.5 Hz, 3H).

3(S orR)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid ethyl ester & 3(R orS)-(quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8-naphthyridin-2-yl)-nonanoicacid ethyl ester (15-6a & 15-6b)

[1286] A solution of 15-5 (1.0 g, 2.25 mmol) in EtOH was treated with10% Pd on C (200 mg) and the mixture stirred under a hydrogen gas-filledballoon for 3 hours. The catalyst was removed by filtration throughcelite and the solvent evaporated to afford the mixture of enantiomersas a colorless glass.

[1287] R_(f) (Silica, 5% MeOH/CH₂Cl₂)=0.25. ¹H NMR (300 MHz, CDCl₃)δ8.81 (d, J=1.8 Hz, 1H), 8.60 (br, s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.96(d, J=1.8 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.54(t, J=7.5 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 6.25 (d, J=7.32 Hz, 1H), 4.05(m, 2H), 3.40 (m, 2H), 3.25 (m, 1H), 2.75 (m, 2 H), 2.65 (m, 2H),2.58(m, 2H), 1.87 (m, 2H), 1.81 (m, 2H), 1.75 (m, 2H), 1.25(m, 4 H), 1.08(t, J=7.5 Hz, 3H).

[1288] The enantiomers 15-6a and 15-6b were separated on a 250×20 mmChiralpak AD column (flow=8 mL/min, A:B=50:50) (A=0.1%diethylamine/hexane, B=1-propanol). R_(t) (15-6a)=18.8 min, (15-6b)=20.9min.

3(R orS)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid (15-7a)

[1289] A solution of 15-6a (193 mg, 0.43 mmol) in 50% aqueous THF (10mL) was treated with solid LiOH (27 mg, 0.65 mmol), and the mixturestirred at room temperature for 18 h, then neutralized with 1N HCl.Chromatography on silica gel (50% A:50% EtOAc) (A=20:1:1 EtOH:NH₄OH:H₂O) afforded 15-7a as a colorless glass.

[1290] R_(f) (Silica, 50% A: EtOAc)=0.45. ¹H NMR (300 MHz, CDCl₃) δ10.2(br, s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.96 (d,J=1.8 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.54 (t,J=7.5 Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 6.25 (d, J=7.32 Hz, 1H), 5.6 (m,2H), 3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2 H), 2.65 (m, 2H),2.58 (m,2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45(m, 2 H).

3(S orR)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid (15-7b)

[1291] This compound was prepared from 15-6b as described above for15-7a.

5-Bromo-2-methoxypyridine (16-2)

[1292] To a solution of KOH (4.2 g, 0.075 mol) in water (750 mL) wasadded 2-methoxypyridine 16-1 (16.4 g, 0.15 mol) followed by a dropwiseaddition of bromine (24 g, 0.15 mol) in 1N aqueous KBr (750 mL) and theresulting solution was stirred at room temperature for 5 hr. SolidNaHCO₃ was added until basic and the solution was extracted with CHCl₃(3×500 mL). The organic layer was washed with 10% NaHSO₃, then brine,dried over Na₂SO₄, filtered, and the solvent removed in vacuo. Theresulting dark brown oil was predominantly the desired compound 16-2 andwas used as such in the next step.

[1293]¹H NMR (300 MHz, CDCl₃) δ3.91 (3H, s), 6.66 (1H, d), 7.62 (1H,dd), 8.20 (1H, d).

Ethyl 3-(6-methoxypyridin-3-yl)acrylate (16-3)

[1294] A solution of the 5-bromo-2-methoxypyridine 16-2 (74.3 g, 0.4mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10minutes. The mixture was heated at 90° C. for 12 hr, then the volatileswere removed in vacuo. Toluene (300 mL) was added and the mixtureconcentrated again. Diethyl ether (300 mL) was added and the mixturefiltered through a pad of silica gel eluting with 800 mL of diethylether. After removal of the diethyl ether, the residue waschromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14then 1:9 to give 16-3 as a yellow solid.

[1295]¹H NMR (300 MHz, CDCl₃) δ1.34 (3H, t), 3.97 (3H, s), 4.26 (2H, q),6.34 (1H, d),6.76 (1H, d), 7.63 (1H, d), 7.77 (1H, dd),8.27 (1H, d).

N-Benzyl-(R)-α-methylbenzyl-3(S)-(6-methoxypyridin-3-yl)-β-alanine ethylester (16-4)

[1296] To a solution of N-benzyl-(R)-α-methylbenzylamine (97.5 g, 462mmol) in THF (750 mL) at 0° C. was added n-butyllithium (2.5M inhexanes; 178.5 mL, 446 mmol). The dark violet solution was stirred at 0°C. for 20 minutes, cooled to −78° C., and the ester 16-3 (63.7 g, 308mmol) in THF (250 mL) was added over 60 minutes. The resulting solutionwas stirred at −78° C. for 1 hr, then cannulated into saturated NH₄Cland extracted with EtOAc, washed with water then brine, dried andconcentrated in vacuo to give an oil. Column chromatography (silica gel;hexane/EtOAc 9:1 then 4:1) gave 16-4 as an oil contaminated withN-benzyl-(R)-α-methylbenzylamine. This oil was taken up in 5% AcOH inwater and extracted with diethyl ether (4×). The organic layers weredried over MgSO₄ and the solvent removed to give the title compound16-4.

[1297]¹H NMR (300 MHz, CDCl₃) δ1.08 (3H, t), 1.27 (3H, d), 2.52 (1H,dd), 2.62 (1H, dd), 3.66 (1H, d), 3.70 (1H, d), 3.93 (3H, s), 3.95 (2H,m), 4.41 (1H, dd), 6.74 (1H, d), 7.15-7.45 (1OH, m), 7.64 (1H, dd), 8.15(1H, d).

3(S)-(6-methoxypyridin-3-yl)-β-alanine ethyl ester (16-5)

[1298] To a degassed (argon) solution of the ester 16-4 (70 g) in EtOH(250 mL), HOAc (25 mL) and water (2 mL) was added 20% Pd(OH)₂ on carbon.The mixture was placed under hydrogen gas using a balloon and theresulting mixture was stirred for 24 hr. After filtration through celite(washing with EtOAc), the solvent was removed in vacuo to afford a waxysolid. This was dissolved in 200 mL water and extracted with diethylether (2×200 mL). The aqueous layer was then treated with solid K₂CO₃until fully saturated and extracted with EtOAc (4×200 mL). After dryingover MgSO₄, the solvent was removed in vacuo to give the title compound16-5 as an oil which solidified in the freezer.

[1299]¹H NMR (300 MHz, CDCl₃) δ1.23 (3H, t), 2.61 (1H, dd), 2.68 (1H,dd), 3.92 (3H, s), 4.15 (2H, q), 4.41 (1H, dd), 6.93 (1H, d), 7.62 (1H,dd), 8.13 (1H, d).

3(S)-(6-Methoxy-pyridin-3-yl)-3-(4-nitro-benzenesulfonylamino)-propionicacid ethyl ester (16-6)

[1300] A solution of aminoester 16-5 (3.0 g, 13.0 mmol) in CH₂Cl₂ (20mL) was treated with aq NaHCO₃ (4.4 g in 20 mL H₂O).2,4-Dinitrobenzenesulfonyl chloride (4.3 g, 16 mmol) was added and thereaction mixture stirred for 12 h. The solution was extracted withCH₂Cl₂ (3×40 mL) and the combined organic solutions washed with satd aqNaHCO₃ (40 mL) and brine (40 mL). The solution was dried over MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (97:3 CH₂Cl_(2/)MeOH) to give the desired product 16-6.

[1301] TLC Rf=0.45 (5% methanol/dichloromethane).

3(S)-(6-Methoxy-pyridin-3-yl)-3-[methyl-(4-nitro-benzenesulfonyl)-amino]-propionicacidethyl ester (16-7)

[1302] Triphenylphosphine (3.9 g, 15 mmol) was added to a solution ofsulfonamide 16-6 (4.5 g, 10 mmol) in THF (30 mL). To this solution wasadded a solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) inTHF/MeOH (10 mL/2.02 mL). A vigorous exotherm occurred and the reactionwas stirred overnight at room temperature. The dark mixture wasconcentrated. The dark oily residue was purified by flash chromatography(40% EtOAc/hexanes) to give the desired product 16-7.

[1303] TLC Rf=0.37 (40% ethyl acetate/hexanes).

3(S)-(6-Methoxy-pyridin-3-yl)-3-methylamino-propionic acid ethyl ester(16-8)

[1304] A solution of sulfonamide 16-7 (4.7 gm, 10 mmol) in CH₂Cl₂ (50mL) was treated with triethylamine (2.8 mL, 20 mmol) and mercaptoaceticacid (1.04 mL, 15 mmol). The reaction was stirred for 90 min at roomtemperature. The green solution was diluted with EtOAc (500 mL) andwashed with satd aq NaHCO₃ (150 mL), water (3×100 mL), and brine (3×100mL). The solution was dried over Na₂SO₄, filtered and concentrated to ablack oil. The residue was purified by flash chromatography (5%MeOH/CH₂Cl₂) to give the desired product 16-8.

[1305]¹HNMR (300 MHz, CDCl₃) δ8.07 (d, J=2.4 Hz, 1H), 7.57 (m, 1H), 6.73(m, 1H), 4.11 (q, J=7.3 Hz, 2H), 3.93 (s, 3H), 2.72 (m, 2H), 1.21 (t,J=7.3 Hz, 3H) ppm

3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b]1,8]naphthyridin-8-yl-propionyl)-amino]-propionicacid ethyl ester (16-9)

[1306] Racemic tricyclic ester 14-3 was resolved by chiral HPLC(Chiracel OD column; 25×2 mm eluting with 95:5 hexanes/isopropanol/0.1%diethylamine at a flow rate of 8 ml/min: R_(T)=6.48 and 7.21 min.) Themore polar enantiomer was hydrolyzed to give carboxylate 14-4a. Asolution of 14-4a (0.175 gm, 0.62 mmol) in DMF/1N HCl (10 mL/0.62 mL)was treated with disopropylethylamine (0.540, 3.10 mmol), aminoester16-8 (0.162 gm, 0.68 mmol) in DMF (2 mL), and PyCLU (0.224 gm, 0.62mmol). After stining for 12 h at room temperature, the solution wasconcentrated and the residue partitioned between EtOAc (20 mL) and satdaq NaHCO₃ (20 mL). The organic solution was washed with brine (10 mL),dried over sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (5% MeOH/CH₂Cl₂) to give the desiredamide 16-9.

[1307] TLC R_(f)=0.28 (5% methanol/dichloromethane).

3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl-propionyl)-amino]propionicacid (16-10)

[1308] A solution of ester 16-9 (0.133 gm, 0.28 mmol) in MeOH/THF/H₂O (1mL/1 mL/1 mL) was treated with 1N aq NaOH (0.56 mL, 0.56 mmol). Afterstirring for 12 h at room temperature, the mixture was concentrated andthe resulting aqueous residue neutralized with 1N aq HCl (0.56 mL). Theresidue was purified by flash chromatography (15% EtOH/15% EtOAc/1% aqNH₄OH/1% H₂O) to give the desired acid 16-10.

[1309]¹HNMR (300 MHz, CDCl₃) mixture of rotamers: δ8.07 (m, 1H), 7.62(m, 1H), 7.35 (m, 1H), 6.80 (m, 1H), 6.38 (m, 1H), 4.90 (s, 3H), 3.45(m, 1H), 3.78 (m, 13H), 1.93 (m, 7H), 1.42 (m, 1H) ppm.

3-Benzyloxycarbonylamino-2-(3-fluoro-phenyl)-propionic acid ethyl ester(17-2)

[1310] To a stirred solution of LDA (9.43 mL of a 2.0 M solution in THF,18.86 mmol) in THF (80 mL) at −78° C. was added a solution of3-fluorophenylacetic acid ethyl ester 17-1 (3.12 g, 17.15 mmol) in THF(5 mL). After 10 min, a solution of the aminomethylbenzotriazole (4.8gm, 17.15 mmol) in THF (5 mL) was added and the solution was slowlywarmed to room temperature over 5 h. The reaction was quenched with satdaq NH₄Cl, extracted with EtOAc (3×40 mL) and the combined organicsolutions washed with brine (50 mL). The organic solution was dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography (20% ethyl acetate/hexanes) to give the desired product17-2.

[1311] TLC R_(f)=0.19 (20% ethyl acetate/hexanes).

2-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid (17-5)

[1312] A solution of ester 17-2 (0.47 gm, 1.36 mmol) in EtOH (15 mL) waspurged with argon and treated with Pd/C (0.047 gm). The heterogeneousmixture was placed under 1 atm of H₂ for 12 h. The mixture was filteredthrough Celite and concentrated to give amine 17-3 (0.30 g, 100%) as apale yellow oil. A stirred solution of acid 1-6 (0.09 g, 0.33 mmol),amine 17-3 (0.071, 0.33 mmol), and N-methylmorpholine (0.11 mL, 0.99mmol) in CH₃CN (5 mL) was treated with BOP-reagent (0.15 g, 0.33 mmol).After stirring for 12 h at room temperature, the mixture wasconcentrated and the residue redissolved in CH₂Cl₂ (30 mL). The organicsolution was washed with satd aq NaHCO₃ (10 mL) and brine (10 mL). Thesolution was dried over Na₂SO₄, filtered and concentrated to give 0.140gm of the crude adduct 17-4. Ester 17-4 (0.140 gm, 0.33 mmol) wasdissolved in MeOH/THF (2 mL/5 mL) and treated with aq 1N LiOH (1.0 mL).The solution was stirred for 12 h at room temperature. The desiredproduct was purified by preparative HPLC (95:5 to 5:95 H₂O/MeCNgradient) to give the acid 17-5.

[1313]¹H NMR (300 MHz, CD₃OD) δ7.58 (d, J=7.6 Hz, 1H), 7.33 (m, 1H),7.13 (m, 3H), 6.59 (d, J=7.6 Hz, 1H), 3.89 (t, J=7.3 Hz, 1H), 3.64 (m,2H), 3.56 (m, 2H), 2.80 (t, J=6.1 Hz), 2.65 (m, 2H), 2.19 (m, 2H), 1.96(m, 2H), 1.58 (m, 4H) ppm.

6-Methoxy-pyridine-3-carboxaldehyde (18-2)

[1314] A solution of n-butyllithium (3.46 mL of a 1.6 M solution inhexanes) in THF (18 mL) was cooled to −78° C. and treated with asolution of 5-bromo-2-methoxypyridine (Johnson, C. R.; Sirisoma, N. S.Tetrahedron Lett. 1998, 39, 2059) 18-1 (1.04 g, 5.53 mmol) in THF (2mL). The heterogeneous mixture was stirred for 40 min and neat DMF (1.5mL) was added. The solution was stirred for 90 min at −78° C. andquenched with satd aq NH₄Cl solution (2 mL). The cold bath was removedand the mixture warmed to room temperature. The mixture was extractedwith EtOAc (2×30 mL) and the combined organic solutions washed withbrine, dried over MgSO₄, filtered, and concentrated to the desiredaldehyde 18-2.

[1315]

[1316] TLC Rf=0.45 (10% ethyl acetate/hexanes).

3-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid (18-3)

[1317] The 6-methoxypyridine carboxaldehyde 18-2 was transformed to acid18-3 as per Scheme 15.

[1318]¹H NMR (300 MHz, CD₃OD) δ8.31 (m, 1H), 8.19 (s, 1H), 7.59 (m, 1H),7.45 (m, 1H), 6.60(m, 1H), 4.16 (s, 3H), 3.51 (m, 2H), 3.20 (m, 1H),2.79 (m, 6H), 1.95 (m, 2H), 1.71 (m, 4H), 1.37 (m, 3H) ppm.

3(R orS)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid and 3(S orR)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (19-3a and 19-3b)

[1319] The 5-pyrimidine carboxaldehyde 19-1 (Rho, T.; Abuh, Y. F.,Synthetic Comm. 1994, 24, 253) was converted into to acid 19-2 as perScheme 15. Separation of the enantiomers of racemic ethyl ester 19-2 wasaccomplished by HPLC (Chiralcel OD; 25×2 mm column; 90/10 to 40/60hexanes/isopropanol/0.1% diethylamine over 60 minutes at a flow rate of7.0 mL/min) to give the two enantiomers (R_(T)=7.79 min and 8.72 min).Hydrolysis of the resulting optically active esters as per Scheme 15provided acids 19-3a and 19-3b.

[1320]¹H NMR (300 MHz, CD₃OD) δ9.01 (s, 1H), 8.71 (s, 2H), 7.57 (d,J=7.4 Hz, 1H), 6.59 (d, J=7.4 Hz, 1H), 3.49 (m, 2H), 3.12 (m, 1H), 2.72(m, 6 H), 1.96 (m, 2H) 1.72 (m, 4H) 1.30 (m, 6H) ppm.

Benzofuran-6-ol (20-2)

[1321] To a solution of 6-hydroxy-[2H]-benzofuran-3-one 20-1 (7.84 g,62.2 mmol) in DMF (100 mL) at room temperature was added triethylamine(8.17 g, 80.9 mmol) and tert-butyldimethylsilyl chloride (10.32 g, 68.4mmol). After stirring for 2 h, the solution was diluted with Et₂O (300mL) and washed with satd aq NH₄Cl (150 mL) and brine (100 mL). Thesolution was dried over MgSO₄, filtered and concentrated to give thebenzofuranone as a yellow oil which solidifed upon standing and was notfurther purified. A solution of this ketone (44.2 g, 167 mmol) in 400 mLMeOH was treated with NaBH₄ (9.5 g, 251 mmol, 1.5 equiv) in fourequivalent portions at room temperature until complete by TLC (˜1 h).The reaction mixture was quenched by the addition of acetone (10 mL).This mixture was then treated with 3 N aq HCl (200 mL) at roomtemperature until complete by TLC (˜24 h). The resulting solution wasconcentrated in vacuo to 150 mL and was extracted with EtOAc (2×250 mL).The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(30% EtOAc/hexanes) affording phenol 20-2 (99%).

[1322] TLC Rf=0.35 (30% ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃)δ7.53 (d, J=1.5 Hz, 1H); 7.41 (d, J=6.3 Hz, 1H); 7.1 (br s, 1H),6.81-6.78 (dd, J=1.5, 6.3 Hz, 1H), 6.69 (d, J=1.5 Hz, 1H) ppm.

Trifluoromethanesulfonic acid benzofuran-6-yl ester (20-3)

[1323] A solution of benzofuran-6-ol 20-2 (4.00 g, 29.85 mmol) andN-phenyltriflimide (10.66 g, 29.85 mmol) in CH₂Cl₂ (150 mL) cooled to 0°C. was treated with triethylamine (5.37 mL, 3.92 g, 38.81 mmol). Thereaction was warmed to room temperature over 90 min and diluted withEt₂O (200 mL). The organic solution was washed with satd aq NH₄Cl (100mL) and brine (100 mL). The solution was dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography (5%EtOAc/hexanes) to give the triflate 20-3 as a colorless oil whichsolidified upon standing.

[1324] TLC Rf=0.39 (10% ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃)δ7.72 (d, J=1.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.48 (br s, 1H), 7.20(dd, J=8.4, 1.0 Hz, 1H), 6.82 (br s, 1H) ppm

Benzofuran-6-carbaldehyde (20-4)

[1325] A solution of triflate 20-3 (0.798 g, 3.0 mmol), Pd(OAc)₂ (13.5mg, 0.060 mmol), and diphenylphosphinopropane (24 mg, 0.060 mmol) in DMF(15 mL) was heated to 70° C. with a gentle flow of CO (g) passingthrough it. Triethylamine (1.66 mL, 12 mmol) was added followed bytrioctylsilane (2.70 mL, 6.0 mmol). The solution was maintained at 70°C. for 2 h, and cooled to room temperature. The solution was dilutedwith water (10 mL). The mixture was extracted with Et₂O (2×30 mL). Thecombined organic extracts were washed with brine (10 mL), dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography (5% acetone/hexanes) to give the desired aldehyde 20-4.

[1326] TLC Rf=0.39 (10% ethyl acetate/hexanes).

3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,]naphthyridin-2-yl)-nonanoicacid (20-5)

[1327] The aldehyde 20-4 was converted into acid 20-5 as per Scheme 15.¹H NMR (300 MHz, CDCl₃) δ7.3 (m, 1H); 7.11 (m, 1H); 6.8 (m, 1H), 6.62(s, 1H), 6.35 (m, 1H), 4.5 (m, 2H), 3.51 (m, 2H), 3.15 (m, 3H), 2.61 (m,5H), 1.91 (m, 3H), 1,72 (m, 4H), 1.4 (m, 6H) ppm.

[4-(Methoxy-methyl-carbamoyl)-butyl]-carbamic acid tert-butyl ester(21-2)

[1328] N-Boc-aminovaleric acid 21-1 (92 mmol) was dissolved in CH₃CN(300ml) and then treated with HCl.HN(Me)OMe (10.8 g, 110 mmol), EDC(17.6g, 92 mmol), HOBT (12.4 g, 92 mmol) and NMM (61 mL, 552 mmol). Themixture was stirred for 18 hours and then concentrated. The residue wasdissolved in ethyl acetate, washed with H₂O, 10% KHSO₄, sat. NaHCO₃,brine, dried (MgSO₄), and concentrated to give amide 21-2 as a brownoil.

[1329] TLC R_(f)=0.67 (silica, ethyl acetate) ¹H NMR (300 MHz, CDCl₃)δ4.66 (s, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 3.13 (t, 2H, 6Hz), 2.45 (m,2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.44 (s, 9H).

(5-Oxo-5-quinolin-3-yl-pentyl)-carbamic acid tert-butyl ester (21-3)

[1330] To a stirred solution of 3-bromoquinoline (25 g, 120 mmol) indiethyl ether −78° C. was added nBuLi (2.5M THF, 48 ml, 120 mmol)dropwise over 30 minutes. After 30 minutes, 21-2 (3.9 g, 15 mmol),dissolved in 50 ml ether was added dropwise over 10 minutes. After 30minutes, the cooling bath was removed. After 1.0 hour, the reaction wasquenched with sat. NH₄Cl. The organic portion was separated, washed withbrine, dried (MgSO₄) and concentrated. The residue was chromatographed(silica gel, 20-50% ethyl acetatel hexanes) to give 21-3 as a yellowsolid.

[1331] TLC R_(f)=0.33 (silica, 50% ethyl acetate/hexanes)

7-tert-butoxycarbonylamino-3-quinolin-3-yl-heptanoic acid methyl ester(21-5)

[1332] To a stirred solution of trimethylphosphonoacetate (6.7 g, 36.5mmol) and THF at 0° C. was added NaHMDS (1.0M THF, 37 ml, 37 mmol)dropwise over 30 minutes. After 30 minutes, 21-3 (3.0 g, 9.13 mmol),dissolved in 100 ml THF, was added. The reaction was heated to reflux.After 1.0 hour, the reaction was diluted with diethyl ether and thenwashed with sat. NaHCO₃, brine, dried (MgSO₄) and concentrated. Theresidue was chromatographed (silica gel, 50%ethyl acetate/hexanes) togive 21-4 as a yellow oil. A mixture of 21-4 (3.5 g, 9.13 mmol) and 10%Pd/carbon (1.0 g) in CH₃OH (50 mL) was stirred under a balloon ofhydrogen for 6 hours. Following filtration and evaporative removal ofthe solvent, the residue was chromatographed (silica gel, 30-50% ethylacetate/hexanes) to give 21-5 as a yellow oil.

[1333] TLC R_(f)=0.43 (silica, 50% ethyl acetate/hexanes) ¹H NMR (300MHz, CDCl₃) δ8.79 (d, 1H, J=2Hz), 8.08 (d, 1H, J=9Hz), 7.93 (s, 1H),7.79 (d,1H, J=8Hz), 7.68 (m,1H), 7.54 (m, 1H), 4.47 (s,1H), 3.57 (s,3H), 3.30 (m, 1H), 3.04 (m,2H), 2.73 (m, 2H), 1.78 (m,2H), 1.45 (m,2H),1.39 (s, 9H), 1.26 (m, 2H).

7-[(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-3-(guinolin-3-yl)-heptanoicacid methyl ester (21-7)

[1334] Ester 21-5 (9.1 mmol) was dissolved in 4M HCl/dioxane (10 ml),stirred for 30 minutes and then concentrated to give the amine 21-6 as ayellow oil. A mixture of 21-6 (900 mg, 2.5 mmol),3-formyl-5,6,7,8-tetrahydro-[1,8]naphthyridine (405 mg, 2.5 mmol),powdered molecular sieves (2 g), DIPEA (0.35 ml, 2.5 mmol) and DCE (100mL) was stirred for 30 minutes. The mixture was cooled to 0° C. and thenNa(OAc)₃BH (730 mg, 3.5 mmol) was added. After 1 hour, the reaction wasdiluted with EtOAc and then washed with sat NaHCO₃, brine, and driedover MgSO₄.

[1335] Following evaporative removal of the solvent, the residue waschromatographed (silica gel, 10% [10:10:1 EtOH/NH₄OH/H₂O]/70:20:10chloroform/ethyl acetate/MeOH] to give 21-7 as a yellow oil.

[1336]¹H NMR (300 MHz, CDCl₃) δ8.79 (d, 1H, J=2Hz), 8.08 (d, 1H, J=9Hz),7.93 (d, 1H, J=2Hz), 7.78 (d, 1H, J=8Hz), 7.67 (m, 1H), 7.54 (m, 1H),7.05 (d, 1H, J=7Hz), 6.39 (d, 1H, J=7Hz), 4.83 (s, 1H), 3.58 (s, 2H),3.57 (s, 3H), 3.34 (m, 3H), 2.73 (m, 4H), 2.53 (t, 2H, J=7Hz), 1.89 (m,2H),1.78 (m, 2H), 1.52 (m, 2H), 1.24 (m, 2H).

7-[(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-ylmethyl)-amino]-3-(quinolin-3-yl)-heptanoicacid (21-8)

[1337] To a solution of 21-7 (0.8255 mmol) in EtOH (5 mL) was added 1NNaOH (1.0 ml, 1.0 mmol). After stirring for 1 hour, the solvents wereevaporated and the residue was chromatographed (silica gel, 20:10:1:1followed by 15:10:1:1 ethyl acetate/EtOH/water/NH₄OH) to give 21-8 as awhite solid.

[1338] TLC Rf=0.10 (10:10:1:1 ethyl acetate/EtOH/water/NH₄OH). ¹H NMR(300 MHz, CD₃OD) δ8.78 (d, 1H, J=2Hz), 8.20 (d, 1H, J=2Hz), 7.97 (d, 1H,J=9Hz), 7.89 (d, 1H, J=8Hz), 7.71 (m, 1H), 7.58 (m, 1H), 7.16 (d, 1H,J=7Hz), 6.43 (d, 1H, J=7Hz), 3.96 (s, 2H), 3.36 (m, 2H), 2.94 (m, 2H),2.65 (m, 2H), 1.83 (m, 5H),1.69 (t, 2H, J=8Hz), 1.30 (m, 2H).

4-(Quinolin-3-yl)-but-3-en-2-one (22-1)

[1339] Dimethyl (2-oxopropyl)phosphonate (3.1 g,19.1 mmol), anhydrousLiCl (972 mg, 23 mmol), and 3-quinoline carboxaldehyde 6-1 (3.0 g,19.1mmol) in anhydrous acetonitrile (70 mL), was treated with DBU (2.9 mL,19.1 mmol) and the resulting suspension stirred at room temperature for1 h. The solvent was removed at reduced pressure and the resultingresidue partitioned between brine and methylene chloride. The organiclayer was removed, dried, and concentrated to afford a yellow solidwhich was recrystallized from ethyl acetate/hexanes to afford 22-1 as anoff-white solid.

[1340]¹H NMR (300 MHz, CDCl₃) δ9.05 (d, J=1.8 Hz, 1H), 8.35 (d, J=1.8Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.75 (t, J=7.5Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 6.53 (d, J=16Hz, 1H), 1.44 (s, 3H). ¹H NMR (300 MHz, CDCl₃) d 9.05 (d, J=1.8 Hz, 1H),8.13 (d, J=8.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H),7.73 (t, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 6.75 (d, J=16 Hz, 1H),6.53 (dd, J=16, 5.8 Hz, 1H),4.56 (m, 1H), 1.44 (d, J=4.6 Hz, 3H).

4-(Quinolin-3-yl)-but-3-en-2-ol (22-2)

[1341] A solution of 22-1 (1.2 g, 6.1 mmol) in anhydrous THF (50 mL) wascooled to −78°, then treated dropwise with i-Bu₂AlH (12.75 mL, 12.2mmol). The resulting solution was stirred at −78° for 20 min, thenquenched with ethyl acetate (20 mL), warmed to room temperature, treatedwith 1 M potassium sodium tartrate (25 mL) and stirred for 4 h. Themixture was extracted with ethyl acetate (2×150 mL) dried, filtered andevaporated to afford 22-2 as a yellow oil.

[1342] R_(f) (Silica, EtOAc)=0.30. ¹H NMR (300 MHz, CDCl₃) δ9.05 (d,J=1.8 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.81 (d,J=7.5 Hz, 1H), 7.73 (t, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 6.75 (d,J=16 Hz, 1H), 6.53 (dd, J=16, 5.8 Hz, 1H),4.56 (m, 1H), 1.44 (d, J=4.6Hz, 3H).

3-(Quinolin-3-yl)-hex-4-enoic acid ethyl ester (22-3)

[1343] A solution of the allylic alcohol 22-2 (1.2 g, 6.1 mmol) intriethyl orthoacetate (50 mL) was treated with propionic acid (0.022 mL,0.31 mmol) and refluxed for 2 h. The cooled mixture was treated with asolution of 1:1 sat. brine/1N HCl (150 mL), then extracted with CH₂Cl₂(3×125 mL). The pooled organic extracts were washed with sat. NaHCO₃,dried, filtered and evaporated. Chromatography on silica gel (EtOAc)afforded 22-3 as a yellow glass.

[1344] R_(f) (Silica,EtOAc)=0.65. ¹H NMR (300 MHz, CDCl₃) δ8.92 (d,J=1.8 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.82 (d,J=7.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 5.6 (m,2H), 4.21 (m, 1H), 4.05 (t, J=7.4 Hz, 2H), 2.79 (m, 2 H),1.91 (d, J=6Hz, 2H), 1.08 (t, J=7.4 Hz, 3H).

4-Oxo-3-(quinolin-3-yl)-butyric acid ethyl ester (22-4)

[1345] A solution of 22-3 (1.0 g, 3.7 mmol), TFA (0.06 mL, 3.9 mmol),and sudan red (0.5 mg) in anhydrous CH₂Cl₂ (50 mL) was cooled to −78°and treated with O₃ until the sudan red color disappeared (5 min). SolidPh₃P (1.4 g, 5.6 mmol) was added and the solution warmed to roomtemperature. After 30 min., the solution was washed with sat. NaHCO₃,dried, filtered, and evaporated. Chromatography on silica gel (10%acetone/EtOAc) afforded 22-4 as colorless glass.

[1346] R_(f) (Silica,EtOAc)=0.25. ¹H NMR (300 MHz, CDCl₃) δ9.88(s, 1H),8.82 (d, J=1.8 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H),7.82 (d, J=7.5 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H),4.4 (m, 1H), 4.05 (t, J=7.4 Hz, 1H), 4.13 (m, 2H), 3.30 (dd, J=7.6, 16Hz, 1H), 2.87 (dd, J=7.2, 16 Hz, 1H), 1.20 (m, 3H).

2-Oxo-5-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-pentyl-phosphonicacid dimethyl ester (22-5)

[1347] A solution of dimethyl methylphosphonate (10.0 g, 80.5 mmol) inanhydrous THF (125 mL) was cooled to −78° and treated dropwise with 2.5M n-BuLi (32.2 mL). After stirring at −78° for 45 min, a solution ofester 22-4 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and theresulting solution stirred for 30 min at −78°, quenched with sat. NH₄Cl(100 mL), then extracted with ethyl acetate (3×150 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and concentrated toafford a yellow oil. Chromatography on silica gel (5% MeOH/CH₂Cl₂)afforded 22-5 as a yellow oil.

[1348] R_(f) (Silica, 5% MeOH/CH₂Cl₂)=0.20. ¹H NMR (300 MHz, CDCl₃)δ7.05 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.32 Hz, 1H), 4.80 (br, s, 1H), 3.81(s, 3H), 3.75 (s, 3H), 3.4 (m, 2H), 3.08 (d, J=22.7 Hz), 2.72 (m, 6 H),2.56 (t, 2 H), 1.91 (m, 2H).

6-Oxo-(3-quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (22-7)

[1349] Ketophosphonate 22-5 (1.0 g, 3.1 mmol), anhydrous LiCl (170 mg,4.0 mmol), and 22-4 (0.797 g, 3.1 mmol) in anhydrous acetonitrile (60mL), was treated with DBU (0.52 mL, 3.3 mmol) and the resultingsuspension stirred at room temperature for 1 h. The solvent was removedat reduced pressure and the resulting residue partitioned between brineand methylene chloride. The organic layer was removed, dried, andconcentrated to afford 22-6 as mixture of E and Z olefins. The crudemixture was dissolved in EtOH (50 mL), treated with 10% Pd/C (200 mg)and stirred under a hydrogen filled balloon for 4 h, then filtered. Thefilrate was treated with LiOH (2.0 eq) and water (20 mL) and stirred atroom temperature for 12 h, then neutralized with 1N HCl and evaporatedChromatography on silica gel (10% MeOH/methylene chloride) afforded 22-7as a white solid.

[1350] R_(f) (Silica,10% MeOH/CH₂Cl₂)=0.20. ¹H NMR (300 MHz, CDCl₃)δ10.9 (br, s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.21(d, J=7.5 Hz, 1H ), 8.05(d, J=1.8 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.58(t, J=7.5 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.3 Hz, 1H), 3.81(m, 1H), 3.44 (m, 2H), 3.0-2.2 (m, 12 H), 1.92 (m, 2H), 1.68 (m, 1H)1.42 (m, 1H).

3-(N-Oxo-quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)nonanoicacid (23-2)

[1351] A solution of 15-6 (100 mg, 0.22 mmol) in 50 aqueous ethanol (30mg) was treated with Oxone® (414 mg, 0.66 mmol) and the resultingsolution stirred at room temperature for 18 h, extracted with CH₂Cl₂(3×60 mL), dried, filtered and evaporated to afford 23-1 as a yellowfilm. Crude 23-1 was hydrolyzed with LiOH and chromatographed on silicagel (50%A:50EtOAc) (A=20:1:1 EtOH: NH₄OH:H₂O) giving 23-2 as a colorlessglass.

[1352] R_(f) (Silica, 50% A: EtOAc)=0.30. ¹H NMR (300 MHz, CD₃OD) δ8.66(d, J=1.8 Hz, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.03(d, J=7.5 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.30(d, J=7.3 Hz, 1H), 6.41 (d, J=7.32 Hz, 1H), 5.6 (m, 2H), 3.56 (m, 1H),3.40 (m, 2H), 2.75 (m, 2 H), 2.65 (m, 2H),2.58 (m, 2H), 2.01 (m, 2H),1.91 (m, 2H), 1.65 (m, 2H), 1.45(m, 2 H).

Furo-[2,3-b]pyridine-5-carboxaldehyde (24-2)

[1353] A solution of alcohol 24-1 (Bhupathy, M.; et al. J. Heterocycl.Chem. (1995), 32, 1283-1287) was treated with excess MnO₂ (10 eq) andthe mixture stirred at room temperature for 16 h, then filtered throughCelite and evaporated to afford 24-2 as a white solid.

[1354] TLC Rf=0.40 (25% EtOAc/Hexane) ¹H NMR (300 MHz, CDCl₃) δ10.22 (s,1H), 9.05 (d, J=1.8 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H) 8.08 (d, J=1.8 Hz,1H), 7.10 (d, J=1.7 Hz, 1H).

3-Furo-[2.3-b]pyridin-5-yl-7-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-(E)-hept-1-en-3-one(24-3)

[1355] Ketophosphonate 15-1 (0.69 g, 2.0 mmol), anhydrous LiCl (86 mg,2.0 mmol), and 24-2 (0.25 g, 1.7 mmol) in anhydrous acetonitrile (25mL), was treated with DBU (0.25 mL, 1.8 mmol) and the resultingsuspension stirred at room temperature for 1 h. The solvent was removedat reduced pressure and the resulting residue partitioned between brineand methylene chloride. The organic layer was removed, dried, andconcentrated to afford a yellow solid which was chromatographed onsilica (5% isopropanol/chloroform) to give 24-3 as an off-white solid.

[1356] R_(f) (Silica, 5% isopropanol/CH₂Cl₂)=0.45. ¹H NMR (300 MHz,CDCl₃) δ8.50 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.75(d, J=2.4Hz, 1H),7.60 (d, J=16 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.83 (d, J=2.4Hz, 1H), 6.77 (d, J=16 Hz, 1H), 6.36 (d, J=7.3 Hz, 1H), 4.85 (br, s,1H), 3.4 (m, 2H), 2.7-2.5 (m, 6 H), 1.91 (m, 2H), 1.68 (m, 4H).

3-(Furo[2.3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-(E)-non-4-enoicacid ethyl ester (24-4)

[1357] 24-3 was converted to 24-4 via the methods taught in theconversion of 15-4 to 15-5.

[1358] R_(f) (Silica, 5% isopropanol/CH₂Cl₂)=0.40. ¹H NMR (300 MHz,CDCl₃) δ8.18 (d, J=2.1 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.36 (d, J=7.3Hz, 1H), 5.6 (m, 2H), 4.85 (br, s, 1H), 4.05 (q, J=7.5Hz, 2H), 4.05 (m,1H), 3.40 (m, 2H), 2.75 (m, 2 H), 2.65 (m, 2H),2.58 (m, 2H), 2.01 (m,2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45(m, 2 H), 1.08 (t, J=7.5 Hz, 3H).

3-(Furo[2.3b]pvridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (24-5a)

[1359] A solution of 24-4 (108 mg, 0.25 mmol) in ethanol was treatedwith 10% Pd/C (30 mg) and stirred under a H₂ filled balloon for 6 h,then filtered through Celite and evaporated. Hydrolysis of the crudeproduct with LiOH and chromatography on silica((50%A:50EtOAc)(A=20:1:1EtOH: NH₄OH:H₂O) afforded 24-5a and 24-5b aswhite solids.

[1360] R_(f) (Silica, 50% A: EtOAc)=0.45. ¹H NMR (300 MHz, CDCl₃) δ10.7(br, s, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H),7.68 (d,J=1.8 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.75 (d, J=1.7 Hz, 1H), 6.25 (d,J=7.3 Hz, 1H), 3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2 H), 2.65 (m,2H),2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45(m, 2H).

3-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (24-5b)

[1361] R_(f) (Silica, 50% A: EtOAc)=0.45. ¹H NMR (300 MHz, CDCl₃) δ10.8(br, s, 1H), 7.85 (d, J=1.8 Hz, 1H),7.40 (d, J=1.8 Hz, 1H), 7.21 (d,J=7.3 Hz, 1H), 6.25 (d, J=7.3 Hz, 1H), 4.60 (t, J=7.4 Hz, 2 H), 3.7 (m,1H), 3.40 (m, 2H),3.20 (t, J=7,4 Hz, 2H), 2.75 (m, 2 H), 2.65 (m,2H),2.58 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45(m, 2H).

2,3-Dihydro-furo[3,2-b]pyridine-5-ethylcarboxylate (25-2)

[1362] A solution of ester 25-1 (Hoffman, Jacob M., Jr. U.S. Pat. No.4,808,595) in ethanol was treated with 10% Pd/C (30 wt %) and stirredunder a hydrogen atmosphere for 22 h, then filtered and evaporated toafford 25-2 as a tan solid.

[1363] TLC Rf=0.40 (25% EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ8.45 (d,J=1.8 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H). 4.72 (t, J=7.5 HZ, 2H), 4.01 (q,J=7.4 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 1.02 (t, J=7.4 Hz,3H).

2,3-Dihydro-furo[3,2b]pyridine-5-methanol (25-3)

[1364] A solution of ester 25-2 (1.93 g, 10 mmol) in anhydrous THF (150mL) was cooled to −78°, then treated dropwise with LAH (10.75 mL, 10.75mmol). The resulting solution was stirred at −78° for 20 min, thenwarmed to 25° and stirred for 4 h, then quenched with ethyl acetate (20mL), treated with 1 M potassium sodium tartrate (25 mL) and stirred for4 h. The mixture was extracted with ethyl acetate (2×150 mL), dried,filtered, and evaporated to afford 25-3 as a white solid which wascarried on without further purification.

[1365] TLC Rf=0.6 (EtOAc). ¹H NMR (300 MHz, CDCl₃) δ8.10 (d, J=1.8 Hz,1H), 7.13 (d, J=1.8 Hz, 1H). 5,10 (s, 2H), 4.65 (t, J=7.5 HZ, 2H), 3.36(t, J=7.5 Hz, 2H).

2,3-Dihydro-furo[3,2b]pyridine-5-carboxaldehyde (25-4)

[1366] A solution of alcohol 25-3 was treated with excess MnO₂ (10 eq)and the mixture stirred at room temperature for 16 h and then filteredthrough Celite and evaporated to afford 25-4 as a white solid.

[1367] TLC Rf=0.35 (25% EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ10.08(s, 1H),8.43 (d, J=1.8 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H). 4.72 (t, J=7.5Hz, 2H), 3.42 (t, J=7.5 Hz, 2H).

3-(2,3-Dihydro-furo[3.2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (25-5)

[1368] Prepared from aldehyde 25-4 using the method described for thepreparation of 15-7.

[1369]¹H NMR (300 MHz, CD₃OD) δ7.80 (d, J=1.5 Hz, 1H), 7.41 (d, J=7.3Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 6.45 (d, J=7.3 Hz, 1H), 4.72 (t, J=7.5Hz, 2H), 3.56 (m, 1H), 3.46 (m, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.75 (m,2H), 2.62 (m, 2H), 2.50 (m, 2H), 1.95 (m, 2H), 1.91 (m, 2H), 1.65 (m,2H), 1.45 (m, 2 H).

4-Iodo-2-methylthiopyrimidine (26-2)

[1370] Chloride 26-1 (10 g, 62.3 mmol) was added dropwise to a 0°solution of 57% HI (50 mL) after 30 min the ice bath was removed, andthe resulting orange suspension stirred at ambient temperature for 16 h.The solution was carefully quenched with sat. sodium bicarbonate (400mL) and the solution adjusted to pH=9 with solid sodium carbonate, andextracted with EtOAc (2×200 mL). The combined organic extracts weredried and evaporated to afford a colorless oil which was dissolved inboiling hexane, then chilled to give 26-2 as colorless needles.

[1371] TLC Rf=0.4 (20%EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ8.01 (d,J=5.1Hz, 1H), 7.41 (d, J=5.1 Hz, 1H). 2.54 (s, 3H).

5-(2-methylthio-pyrimidin-4-yl)-pentanoic acid ethyl ester (26-3)

[1372] A solution of 26-2 (9.5 g, 38 mmol) in DMF (150 mL) was treatedwith Pd(OAc)₂ (0.43 g, 1.9 mmol) and Et₃N (8.0 g, 80 mmol), purged withargon, and the mixture heated to 50° for 16 h. The solvent was removedat reduced pressure and the brown residue partitioned between ethylacetate and sat. sodium bicarbonate. The organic layer was dried,filtered, and evaporated and the residue purified by chromatography onsilica (20%EtOAc/Hexane) to afford 26-3 as an oil.

[1373] TLC Rf=0.3 (20%EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ8.41 (d,J=5.1Hz, 1H), 7.0 (m, 1H), 6.80 (d, J=5.1 Hz, 1H). 6.38 (d, J=15.8 Hz,1H), 4.18 (q, J=7.3 Hz, 2H), 2.7-2.5 (4H), 2.57 (s, 3H), 1.25 (t, J=7.3Hz, 3H).

[1374] This material (5.6 g, 22 mmol) was reduced at 1 atm. H₂ using10%Pd/C (1.2 g, 20 wt. %) in ethanol to afford 26-3 as colorless oil.

[1375] TLC Rf=0.3 (20%EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ8.41 (d,J=5.1Hz, 1H), 6.80 (d, J=5.1 Hz, 1H). 4.18 (q, J=7.3 Hz, 2H), 2.65 (t,J=7.4 Hz, 2H), 2.57 (s, 3H), 2.35 (t, J=7.4 Hz, 2H),1.7 (4H), 1.25 (t,J=7.3 Hz, 3H).

5-(2-methanesulfonyl-pyrimidin-4-yl)-pentanoic acid ethyl ester (26-4)

[1376] To a solution of 26-3 (2.0 g, 8.0 mmol) in MeOH (100 mL) wasadded a solution of Oxone® (14.5 g, 24 mmol) in H₂O (100 mL). Theresulting solution was stirred at ambient temperature for 20 h, then theMeOH was removed at reduced pressure and the aqueous phase diluted withsat. NaHCO₃ (100 mL) and extracted with EtOAc (2×100 mL). The organiclayers were dried, filtered and concentrated to afford 26-4 as acolorless oil.

[1377] TLC Rf=0.3 (20%EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ8.75 (d,J=5.1Hz, 1H), 7.43 (d, J=5.1 Hz, 1H). 4.18 (q, J=7.3 Hz, 2H), 3.37 (s,3H), 2.92 (t, J=7.4 Hz, 2H), 2.37 (t, J=7.4 Hz, 2H), 1.87 (m, 2H), 1.72(m, 2H), 1.25 (t, J=7.3 Hz, 3H).

5-(2-amino-pyrimidin-4-yl)-pentanoic acid (26-5)

[1378] A solution of 26-4 (0.19 g, 0.67 mmol) in THF (5 mL) was cooledto 0° and saturated with NH₃ gas. The mixture was stirred at 0° for 4 h,then evaporated and the residue partitioned between EtOAc and sat.NaHCO₃. The organic layer was dried filtered and concentrated to givethe amino ester 26-5.

[1379] TLC Rf=0.3 (EtOAc). ¹H NMR (300 MHz, CD₃OD) δ8.16 (d, J=5.1Hz,1H), 6.75 (d, J=5.1 Hz, 1H). 4.18 (q, J=7.3 Hz, 2H), 2.58 (t, J=7.4 Hz,2H), 2.35 (t, J=7.4 Hz, 2H),1.7 (4H), 1.25 (t, J=7.3 Hz, 3H).

[1380] The ester obtained above was dissolved in 6N HCl and stirred atambient temperature for 16 h then concentrated to afford 26-5 as its HClsalt.

[1381]¹H NMR (300 MHz, CD₃OD) δ8.53 (d, J=5.1Hz, 1H), 6.85 (d, J=5.1 Hz,1H). 2.58 (t, J=7.4 Hz, 2H), 2.35 (t, J=7.4 Hz, 2H),1.7 (4H).

3-[5-(2-Amino-pyrimidin-4-yl)-pentanoylamino]-3(S)-(quinolin-3-yl)-propionicacid (26-6)

[1382] 26-6 was obtained following the coupling of 26-5 and 5-7 andsubsequent saponification as described for 1-6 and 1-7 to fiunish 1-9.

[1383]¹H NMR (300 MHz, CD₃OD) δ8.53 (s, 1H), 20 (s, 1H), 7.7 (d, J=7 Hz,1H), 7.7-7.4(4H), 6.11 (d, J=5 Hz, 1H), 5.3 (m,1H), 3,5 (m, 3H), 2.5 (m,2H), 2.10 (m, 4H0), 1.51 (m, 2 H), 1.3 (m, 2H).

3-(4-Aminbutyrylamino)-3-(S)-(3-fluorophenyl)-propionic acid ethyl esterhydrochloride (27-2)

[1384] A mixture of 27-1 (245 mg, 1.2mmol), 9-1 (300 mg, 1.21 mmol), EDC(300 mg, 1.57 mmol), NMM (490 mg, 4.84 mmol), and HOBT (213 mg,157 mmol)in DMF (7 mL) was stirred under argon for 16 h, then diluted with EtOAc(50 mL ) and washed successively with sat. NaHCO₃ H₂O, 10% KHSO₄, andbrine (20 mL), dried and concentrated to give the Boc-protected aminoester as an oil.

[1385] TLC Rf=0.7 (90%EtOAc/Hexane). ¹H NMR (300 MHz, CDCl₃) δ7.3 (t,J=7.8 Hz, 1H),7.1 (d, J=7.8 Hz, 1H). 7.07 (d, J=7.8 Hz, 1H). 6.92 (t,J=7.8 Hz, 1H), 5.40 (m, 1H), 4.80 (br, t, 1H), 4.18 (q, J=7.3 Hz, 2H),3.20 (m, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.35 (t, J=7.4 Hz, 2H),1.7 (4H),1.25 (t, J=7.3 Hz, 3H).

[1386] The Boc protected amino ester obtained above (440 mg, 1.1 mmol)was dissolved in 2.3N ethanolic HCl (10 mL) and stirred at ambienttemperature for 3 h then concentrated to afford 27-2 as its HCl salt.

[1387]¹H NMR (300 MHz, CD₃OD) δ7.3 (t, J=7.8 Hz, 1H),7.1 (d, J=7.8 Hz,1H). 7.07 (d, J=7.8 Hz, 1H). 6.92 (t, J=7.8 Hz, 1H), 5.40 (m, 1H), 4.18(q, J=7.3 Hz, 2H), 3.20 (m, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.35 (t, J=7.4Hz, 2H),1.7 (4H), 1.25 (t, J=7.3 Hz, 3H).

3(S)-(3-Fluorophenyl)-3-[4-([1,8]naphthyridin-2-ylamino)butyrylamino]propionicacid ethyl ester (27-4)

[1388] A mixture of amine hydrochloride 27-2 (350 mg, 1.1 mmol), bromide27-3 (230 mg, 1.1 mmol) (for preparation see: Roszkiewicz, W.; Wozniak,M.; Synthesis 1976, 691-2), and DIPEA (355 mg, 2.75 mmol) inacetonitrile (5.5 mmol) was heated at reflux for 20 h. The solution wasconcentrated and the brown residue partitioned between EtOAc and sat.NaHCO₃. The organic layer was washed with brine, dried, filtered,concentrated and the oil chromatographed on silica (5% EtOH/EtOAc) toafford 27-4 as a colorless glass.

[1389] TLC Rf=0.45 (5% EtOH/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ8.80 (d,J=1.8 HZ, 1H), 8.50 (br,d, J-7 Hz, 1H), 7.85 (d,d, J=1.8, 7.0 Hz, 1H),7.75 (d, J=7.5 Hz, 1H). 7.2-6.8 (5H), 6.62 (d, J=7.5 Hz, 1H), 5.61 (m,1H), 5.31 (br, t, 1H), 4.18 (q, J=7.3 Hz, 2H), 3.60 (m, 2H), 3.2 (dd,J=6.0, 10.5 Hz, 1H) 3.02 (dd, J=5.6,10.5 Hz, 1H) 2.22 (t, J=7.4 Hz,2H),1.92 (m, 2H), 1.25 (t, J=7.3 Hz, 3H).

3(S)-(3-Fluorophenyl)-3-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylamino)-butyrylamino]-propionicacid bis trifluoroacetate (27-5)

[1390] A solution of 274 (90 mg, 0.21 mmol) in EtOH (3 ml) was treatedwith 10% Pd/C (60 mg) and the mixture stirred under a H₂ filled balloonfor 24 h. The catalyst was removed by filtration and the filtrateconcentrated to afford crude reduced ester. This material was hydrolyzedwith LiOH , neutralized with 1N HCl, concentrated and the residuepurified by reverse phase chromatography to afford 27-5 as its bis-TFAsalt.

[1391] High resolution Ms Calc'd.=401.1977, Observed=401.1983.

8-Oxo-nonanal (28-2)

[1392] To a cooled (−78° C.) solution of 1-methyl-cyclooctene 28-1 (5.2g, 41.9 mmol) in 200 mL CH₂Cl₂ was introduced ozone for 30 min. Themixture was stirred for 1 hr and purged with argon. It was then treatedwith Ph₃P. The reaction mixture was concentrated and purified by silicagel flash chromatography (EtOAc/hexanxes 1:10) to afford the desiredproduct 28-2 as an oil.

[1393]¹H NMR (400 MHz, CDCl₃) δ9.72 (t, J=2.0 Hz, 1H), 2.38 (m, 4H),2.09 (s, 3H), 1.61-1.52 (m, 4H), 1.28 (m, 4H).

10-Oxo-undec-2-enoic acid ethyl ester (28-3)

[1394] To a cooled (−40° C.) solution of 28-2 (10.8 g, 69.2 mmol) in 150mL CH₂Cl₂ was added (carbethoxymethylene)triphenylphosphorane (24.1 g,69.2 mmol) in 100 mL CH₂Cl₂ gradually over 15 min. The reaction mixturewas stirred for 12 hr while it was warmed up to room temperature. Aftersolvent removal, the residue was purified using silica gel flashchromatography (EtOAc/hexanes: 1:8 to 1:6) to afford the desired product28-3 as an oil.

[1395]¹H NMR (400 MHz, CDCl₃) δ6.95 (m, 1H), 5.80 (d, J=15.6 Hz, 1H),4.18 (d, J=7.2 Hz, 2H), 2.42 (t, J=7.2, 2H), 2.20 (m, 2H), 2.13 (s, 3H),1.57 (m, 2H), 1.46 (m, 2H), 1.29 (m, 7H).

9-[1,8]Naphthyridin-2-yl-non-2-enoic acid ethyl ester (28-4)

[1396] A mixture of 28-3 (4.1 g, 18.3 mmol), proline (2.7 g, 23.8 mmol),and 1-3 (2.9 g, 23.8 mmol ) in 50 mL EtOH was heated at 110° C. for 24hr. The reaction mixture was concentrated and purified by silica gelchromatography (EtOAc, 100%) to afford the desired product 28-4 as asolid.

[1397]¹H NMR (400 MHz, CDCl₃) δ9.08 (dd, J=4.4, 2.0 Hz, 1H), 8.15 (dd,J=8.0, 2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1 H), 7.44 (dd, J=8.0, 4.4, 1H),7.38 (d, J=8.4 Hz, 1H), 6.95 (dt, J=15.6, 7.2 Hz, 1H), 5.80 (dt, J=15.6,1.6Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 2.18 (m,2H), 1.90 (m, 2H), 1.43 (m, 6H), 1.28 (t, J=7.2 Hz, 3H).

3-(6-Amino-pyridin-3-yl)-9-[1,8]naphthyridin-2-yl-non-2-enoic acid ethylester (28-5)

[1398] A mixture of 28-4 (0.3 g, 1.0 mmol), 2-amino-5-bromopyridine (0.3g, 1.9 mmol), KOAc (0.3 g, 2.4 mmol) and Pd(OAc)₂ (0.02 g, 0.1 mmol) in6 mL DMF was purged with argon for 5 min and then heated at 90° C. for 7hr and 115° C. for 48 hr. It was cooled, treated with 50 mL water andextracted with EtOAc (×3). The combined organic layers were washed withbrine and dried over Na₂SO₄. After solvent removal, the residue waspurified using silica gel flash chromatography (100% EtOAc to EtOAc/MeOH10:1) to afford the desired product 28-5 as an oil.

[1399]¹H NMR (400 MHz, CDCl₃) δ9.07 (dd, J=4.4, 2.0 Hz, 1H), 8.18 (d,J=2.0 Hz, 1H), 8.14 (dd, J=8.0, 2.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1 H),7.53 (dd, J=8.8, 2.0 Hz, 1H), 7.44 (dd, J=8.0, 4.4, 1H), 7.38 (d, J=8.4Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 5.96 (s, 1H), 4.83 (bs, 2H), 4.18 (q,J=7.2 Hz, 2H), 3.02 (m, 4H), 1.85 (m, 2H), 1.43 (m, 6H), 1.29 (t, J=7.2Hz, 3H).

3-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid ethyl ester (28-6)

[1400] A mixture of 28-5 (0.1 g, 0.3 mmol) and 10% Pd/C (0.1 g) in 10 mLmethanol was purged with argon under vacuum and then treated underballoon hydrogenation conditions for 40 hr. It was filtered through apad of celite. The solution was concentrated. The residue was purifiedby silica gel chromatography (100% CHCl₃ to CHCl₃/MeOH 5:1) to affordthe desired product 28-6 as an oil.

[1401]¹H NMR (400 MHz, CDCl₃) δ7.88 (d, J=2.0 Hz, 1H), 7.25 (dd, J=8.4,2.0 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.45 (d, J=8.4 Hz, 1 H), 6.31 (d,J=7.6 Hz, 1H), 4.98 (bs, 1H), 4.34 (bs, 2H), 4.04 (q, J=7.2 Hz, 2H),3.39 (m, 2H), 2.95 (m, 1H), 2.68 (m, 2H), 2.60-2.43 (m, 4H), 1.89 (m,2H), 1.64-1.44 (m, 4H), 1.27 (m, 6H), 1.29 (t, J=7.2 Hz, 3H).

3-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (28-7)

[1402] A mixture of 28-6 (0.04 g, 0.1 mmol) and LiOH (1M, 0.3 mL, 0.3mmol) in 1 mL EtOH and 0.5 mL H₂O was stirred for 12 hr at roomtemperature. It was concentrated and diluted with 1N HCl (2 mL). Themixture was purified by reverse phase HPLC (C18 column; gradient:H₂O/CH₃CN/TFA from 95:5:0.1 to 5:95:0.1 over 45 min) to give pure 28-7as the TFA salt.

[1403]¹H NMR (400 MHz, CD₃OD) δ7.90 (dd, J=9.2, 2.0 Hz, 1H), 7.67 (d,J=2.0 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 6.99 (d, J=9.2 Hz, 1 H), 6.55 (d,J=7.6 Hz, 1H), 3.48 (m, 2H),3.00 (m, 1H), 2.80 (m, 2H), 2.66 (m, 5H),2.53 (m, 1H), 1.94 (m, 2H), 1.64 (m, 4H), 1.27 (m, 4H).

Methyl 8-oxo-nonanoate (29-2)

[1404] To a stirred suspension of cuprous cyanide (2.87 g, 32.0 mmol) intetrahydrofuran (100 mL) at −78° C. was added a solution ofmethylmagnesium bromide (9.9 mL of a 3.0 M solution in tetrahydrofuran).The reaction mixture was allowed to warm to −15° C. for 5 minutes andthen cooled to −78° C. To this was added a solution of methyl7-(chloroformyl)-heptanoate 29-1 (4.9 g, 23.7 mmol) in tetrahydrofuran(20 mL) and the reaction mixture was allowed to warm to −10° C. for 1.5hours. To the mixture was added a 9:1 solution of saturated aqueousammonium chloride and concentrated aqueous ammonium hydroxide (200 mL)and the resulting mixture was extracted with ethyl acetate (2×200 mL).The organic extracts were washed successively with saturated aqueousammonium chloride, saturated aqueous sodium hydrogen carbonate, andsaturated aqueous sodium chloride. The organic extracts were then driedwith anhydrous magnesium sulfate, filtered, and concentrated at reducedpressure to give 29-1 as an oil which was used in the next step withoutfurther purification.

7-[1,8]Naphthyridin-2-yl-heptanoic acid methyl ester (29-3)

[1405] To a stirred solution of methyl 8-oxo-nonanoate 29-2 (3.8 g, 20.4mmol) in absolute ethanol (100 mL) was added2-aminopyridine-3-carboxaldehyde (2.49 g, 20.4 mmol) and L-proline (1.17g, 10.2 mmol) and the mixture was heated to 95° C. for 18 hours, afterwhich the mixture was cooled to ambient temperature and thenconcentrated at reduced pressure. The resulting solid was purified byflash column chromatography over silica gel with 95:5 ethylacetate/methanol to give 29-3 as a white solid.

[1406]¹H NMR (300 MHz, CDCl₃) δ9.11 (dd, J=2.0, 4.2 Hz, 1 H), 8.17 (dd,J=1.9, 8.1 Hz, 1 H), 8.14 (d, J=8.4 Hz, 1H), 7.44 (dd, J=4.4, 8.1 Hz,1H), 7.39 (d, J=8.3 Hz, 1H), 3.65 (s, 3H), 3.03 (app t, J=6.2 Hz, 2H),2.32 (app t, J=7.7 Hz, 2H), 1.98-1.84 (m, 2H), 1.70-1.57 (m, 2H),1.50-1.33 (m, 4H).

7-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methylester (29-4)

[1407] To a stirred suspension of 10% palladium on carbon (600 mg) inethanol (25 mL) was added a solution of7-[1,8]naphthyridin-2-yl-heptanoic acid methyl ester 29-3 (3.6 g) inethanol (75 mL) and the mixture was subjected to an atmosphere ofhydrogen for 18 hours. The reaction mixture was filtered through Celiteand concentrated at reduced pressure to give 29-4 as an oil.

[1408]¹H NMR (300 MHz, CDCl₃) δ7.06 (d, J=7.3 Hz, 1H), 6.33 (d, J=7.3Hz, 1H), 5.01 (br s, 1H), 3.66 (s, 3H), 3.42-3.37 (m, 2H), 2.69 (app t,J=6.3 Hz, 2H), 2.53 (app t, J=7.6 Hz, 2H), ), 2.29 (app t, J=7.5 Hz,2H), 1.94-1.86 (m, 2H), 1.67-1.59 (m, 2H), 1.37-1.33 (m, 4H).

3-Oxo-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acidtert-butyl ester (29-5)

[1409] To a stirred solution of diisopropylamine (5.17 mL, 36.9 mmol) inanhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution ofn-butyllithium in hexanes (16.2 mL of a 2.5 M solution). After 5minutes, t-butyl acetate (4.97 mL, 36.9 mmol) was added. After anadditional 5 minutes,7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methylester 29-4 (3.4 g, 12.3 mmol) in tetrahydrofuran (30 mL) was added andthe solution was warmed to −40° C. for one hour. The reaction mixturewas then poured into saturated aqueous sodium hydrogen carbonate, andextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried with anhydrous magnesiumsulfate, filtered, and concentrated at reduced pressure. The resultingoil was purified by flash column chromatography over silica gel withethyl acetate to give 29-5 as a yellowish oil.

[1410]¹H NMR (300 MHz, CDCl₃) δ7.04 (d, J=7.3 Hz, 1H), 6.33 (d, J=7.3Hz, 1H), 4.84 (br s, 1H), 3.42-3.37 (m, 2H), 3.33 (s, 2H), 2.69 (app t,J=6.4 Hz, 2H), 2.58-2.44 (m, 2H), 1.94-1.86 (m, 2H), 1.72-1.52 (m, 4H),1.47 (s, 9H), 1.39-1.28 (m, 4H).

9-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoicacid tert-butyl ester (29-6)

[1411] To a stirred solution of3-oxo-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acidtert-butyl ester 29-5 (1.0 g, 2.77 mmol) in anhydrous tetrahydrofuran(25 mL) at 0° C. was added a solution of potassiumbis(trimethylsilyl)amide in toluene (7.2 mL of a 0.5 M solution). After5 minutes, N-phenyltrifluoromethanesulfonimide (1.49 g, 4.17 mmol) wasadded in one portion and the resulting solution was allowed to warm toambient temperature for 2 hours. The reaction mixture was then pouredinto saturated aqueous sodium hydrogen carbonate and extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried with anhydrous magnesium sulfate, filtered, andconcentrated at reduced pressure. The resulting oil was purified byflash column chromatography over silica gel with 3:2 ethylacetate/hexanes to give 29-6 as a yellowish semi-solid.

[1412]¹H NMR (300 MHz, CDCl₃) δ7.08 (d, J=7.3 Hz, 1H), 6.34 (d, J=7.3Hz, 1H), 5.66 (s, 1H), 5.09 (br s, 1H), 3.44-3.37 (m, 2H), 2.68 (app t,J=6.2 Hz, 2H), 2.56 (app t, J=7.7 Hz, 2H), ), 2.33 (app t, J=7.6 Hz,2H), 1.94-1.83 (m, 2H), 1.70-1.48 (m, 4H), 1.49 (s, 9H), 1.37-1.29 (m,4H).

3-Phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acidtert-butyl ester (29-7a)

[1413] To a stirred solution of9-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoicacid tert-butyl ester 29-6 (100 mg, 0.20 mmol) in toluene (2.5 mL) wasadded palladium(tetrakis)-triphenylphosphine (23 mg, 0.020 mmol),phenylboronic acid (50 mg, 0.41 mmol), and potassium carbonate (56 mg,0.41 mmol). The resulting suspension was heated at 90-100° C. for 2hours, and then was allowed to cool to ambient temperature. The reactionmixture was then poured into saturated aqueous sodium hydrogen carbonateand extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried with anhydrous magnesiumsulfate, filtered, and concentrated at reduced pressure. The resultingoil was purified by flash column chromatography over silica gel with 4:1ethyl acetate/hexanes to give 29-7a as a colorless oil.

[1414]¹H NMR (300 MHz, CDCl₃) δ7.41-7.15 (m, 5H), 7.02 (d, J=7.3 Hz,1H), 6.31 (d, J=7.2 Hz, 1H), 5.77 (br s, 1H), 4.77 (br s, 1H), 3.42-3.34(m, 2H), 2.69 (app t, J=6.3 Hz, 2H), 2.50 (app t, J=7.6 Hz, 2H), 2.39(app t, J=7.8 Hz, 2H), 1.95-1.84 (m, 2H), 1.66-1.54 (m, 4H), 1.42-1.26(m, 8H), 1.21 (s, 9H).

3-Phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acidtert-butyl ester (29-8a)

[1415] To a stirred suspension of 10% palladium on carbon (15 mg) inethanol (2 mL) was added a solution of3-phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acidtert-butyl ester 29-7a (62 mg) in ethanol (3 mL) and the mixture wassubjected to an atmosphere of hydrogen for 6 hours. The reaction mixturewas filtered through Celite and concentrated at reduced pressure to give29-8a as an oil.

[1416]¹H NMR (300 MHz, CDCl₃) d 7.31-7.13 (m, 5H), 7.04 (d, J=7.3 Hz,1H), 6.31 (d, J=7.2 Hz, 1H), 4.92 (br s, 1H), 3.42-3.35 (m, 2H),3.06-2.94 (m, 1H), 2.69 (app t, J=6.2 Hz, 2H), 2.58-2.40 (m, 4H),1.94-1.85 (m, 2H), 1.66-1.48 (m, 4H), 1.36-1.18 (m, 17H).

3-Phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acidhydrochloride (29-9a)

[1417] Hydrogen chloride gas was bubbled into a stirred solution of3-phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acidtert-butyl ester 29-8a (60 mg) in ethyl acetate at 0° C. for one hour.The reaction mixture was allowed to warm to ambient temperature and thenconcentrated at reduced pressure. The resulting solid 29-9a was dried invacuo overnight.

[1418]¹H NMR (300 MHz, CD₃OD) δ7.78 (d, J=7.1 Hz, 1H), 7.33-7.11 (m,5H), 6.58 (d, J=7.2 Hz, 1H), 3.52-3.42 (m, 2H), 3.10-2.96 (m, 1H), 2.82(app t, J=7.0 Hz, 2H), 2.68-2.43 (m, 4H), 1.98-1.89 (m, 2H), 1.76-1.50(m, 4H), 1.40-1.05 (m, 8H).

3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoicacid tert-butyl ester (29-7b)

[1419] To a stirred solution of9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoicacid tert-butyl ester 29-6 (100 mg, 0.20 mmol) in toluene (2.5 mL) wasadded palladium(tetrakis)-triphenylphosphine (23 mg, 0.020 mmol),benzo[b]thiophene-2-boronic acid (50 mg, 0.41 mmol) and potassiumcarbonate (56 mg, 0.41 mmol). The resulting suspension was heated at90-100° C. for 2 hours, and then was allowed to cool to ambienttemperature. The reaction mixture was then poured into saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride, dried withanhydrous magnesium sulfate, filtered, and concentrated at reducedpressure. The resulting oil was purified by flash column chromatographyover silica gel with 4:1 ethyl acetate/hexanes to give 29-7b as acolorless oil.

[1420]¹H NMR (300 MHz, CDCl₃) δ7.82-7.70 (m, 2H), 7.53 (s, 1H),7.39-7.22 (m, 2H), 7.02 (d, J=7.3 Hz, 1H), 6.33 (d, J=7.3 Hz, 1H), 5.89(br s, 1H), 4.78 (br s, 1H), 3.42-3.36 (m, 2H), 2.74 (app t, J=6.2 Hz,2H), 2.58-2.42 (m, 2H), 1.95-1.77 (m, 4H), 1.70-1.10 (m, 17H).

3-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid tert-butyl ester (29-8b)

[1421] To a stirred suspension of 10% palladium on carbon (45 mg) inmethanol (5 mL) was added a solution of3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoicacid tert-butyl ester 29-7b (220 mg) in ethanol (5 mL) and the mixturewas subjected to an atmosphere of hydrogen for 48 hours. The reactionmixture was filtered through Celite and concentrated at reducedpressure. The resulting oil was purified by flash column chromatographyover silica gel with 9:1 ethyl acetate/methanol to give 29-8b as acolorless oil.

[1422]¹H NMR (300 MHz, CDCl₃) δ7.89-7.64 (m, 4H),7.03 (s, 1H), 7.02 (d,J=7.3 Hz, 1H), 6.29 (d, J=7.3 Hz, 1H), 4.85 (br s, 1H), 3.44-3.34 (m,3H), 2.72-2.44 (m, 6H), 1.94-1.84 (m, 2H), 1.72-1.52 (m, 4H), 1.34 (s,9H), 1.33-1.22 (m, 8H).

3-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid (29-9b)

[1423] Hydrogen chloride gas was bubbled into a stirred solution of3-(benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid tert-butyl ester 29-8b (85 mg) in ethyl acetate at 0° C. for onehour. The reaction mixture was allowed to warm to ambient temperatureand then concentrated at reduced pressure. The resulting solid wasneutralized with concentrated ammonium hydroxide, then the resultingfree base was purified by flash column chromatography over silica gelwith 25:3:2 chloroform/ethyl acetate/methanol to give 29-9b as acolorless oil.

[1424]¹H NMR (300 MHz, CD₃OD) d 7.77-7.62 (m, 2H), 7.38 (d, J=7.3 Hz,1H), 7.30-7.18 (m, 2H), 7.09 (s, 1H), 6.45 (d, J=7.2 Hz, 1H),3.60-3.51(m, 1H), 3.41 (app t, J=6.4 Hz, 2H),2.78-2.52 (m, 6H), 1.94-1.56 (m,8H), 1.44-1.28 (m, 8H).

3-(Benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-2-enoicacidtert-butyl ester (29-7c)

[1425] To a stirred solution of benzthiazole (165 mg, 1.22 mmol) inanhydrous tetrahydrofuran (5 mL) at −78° C. was added a solution ofn-butyllithium in hexanes (0.52 mL of a 2.5 M solution). After 5minutes, a solution of zinc chloride in tetrahydrofuran (2.6 mL of a0.50 M solution) was added and the reaction mixture was allowed to warmto ambient temperature. To the resulting solution was added9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoicacid tert-butyl ester 29-6 (400 mg, 0.81 mmol) andpalladium(tetrakis)-triphenylphosphine (94 mg, 0.081 mmol) and themixture was stirred at ambient temperature for 1 hour. The reactionmixture was then poured into saturated aqueous sodium hydrogen carbonateand extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried with anhydrous magnesiumsulfate, filtered, and concentrated at reduced pressure. The resultingoil was purified by flash column chromatography over silica gel with 4:1ethyl acetate/hexanes to give 29-7c as a colorless oil.

[1426]¹H NMR (300 MHz, CDCl₃): δ8.10-7.85 (m, 2H), 7.50-7.35 (m, 2H),7.02 (d, J=7.2 Hz, 1H), 6.35 (d, J=7.2 Hz, 1H), 6.05 (br s, 1H), 5.55(br s, 1H), 3.45-3.36 (m, 2H), 2.74-2.65 (m, 2H), 2.62-2.42 (m, 2H),2.28 (app t, J=7.2 Hz, 2H), 1.95-1.82 (m, 2H), 1.70-1.15 (m, 17H).

3-(Benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid tert-butyl ester (29-8c)

[1427] To a stirred suspension of 10% palladium on carbon (50 mg) inmethanol (5 mL) was added a solution of3-(benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoicacidtert-butyl ester 29-7c (190 mg) in ethanol (5 mL) and the mixturewas subjected to an atmosphere of hydrogen for 48 hours. The reactionmixture was filtered through Celite and concentrated at reducedpressure. The resulting oil was purified by flash column chromatographyover silica gel with 4:1 hexanes/acetone to give 29-8c as a colorlessoil.

[1428]¹H NMR (300 MHz, CDCl₃) δ7.99-7.81 (m, 2H), 7.48-7.31 (m, 2H),7.04 (d, J=7.3 Hz, 1H), 6.30 (d, J=7.2 Hz, 1H), 4.95 (br s, 1H),3.66-3.56 (m, 1H), 3.38 (app t, J=6.3 Hz, 2H), 2.90-2.63 (m, 6H), 2.48(app t, J=7.6 Hz, 2H), 1.94-1.74 (m, 4H), 1.64-1.52 (m, 2H), 1.36 (s,9H), 1.34-1.22 (m, 8H).

3-(Benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride (29-9c)

[1429] Hydrogen chloride gas was bubbled into a stirred solution of3-(benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid tert-butyl ester 29-9b (80 mg) in ethyl acetate at 0° C. for onehour. The reaction mixture was allowed to warm to ambient temperatureand then concentrated at reduced pressure. The resulting solid 29-9c waspumped in vacuo overnight.

[1430]¹H NMR (300 MHz, CD₃OD) δ8.01-7.90 (m, 2H), 7.60-7.41 (m, 3H),6.58 (d, J=7.3 Hz, 1H), 3.78-3.62 (m, 1H), 3.49 (app t, J=6.4 Hz, 2H),2.98-2.59 (m, 6H), 1.97-1.82 (m, 4H), 1.70-1.56 (m, 2H), 1.44-1.28 (m,6H).

N-(4-Iodo-phenylsulfonylamino)-L-asparagine (A-2)

[1431] To a stirred solution of acid A-1 (4.39 g, 33.2 mmol), NaOH (1.49g, 37.2 mmol), dioxane (30 ml) and H₂O (30 ml) at 0° C. was added pipsylchloride (10.34 g, 34.2 mmol). After ˜5 minutes, NaOH (1.49, 37.2 mmol)dissolved in 15 ml H₂O, was added followed by the removal of the coolingbath. After 2.0 h, the reaction mixture was concentrated. The residuewas dissolved in H₂O (300 ml) and then washed with EtOAc. The aqueousportion was cooled to 0° C. and then acidified with concentrated HCl.The solid was collected and then washed with Et₂O to provide acid A-2 asa white solid.

[1432]¹H NMR (300 MHz, D₂O) δ7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz)3.70 (m, 1H), 2.39 (m, 2H).

2(S)-(4-Iodo-phenylsulfonylamino)-β-alanine (A-3)

[1433] To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H₂O (40ml) at 0° C. was added Br₂ (1.30 ml, 24.9 mmol) dropwise over a tenminute period. After ˜5 minutes, acid A-2 (9.9 g, 24.9 mmol), NaOH (2.00g, 49.8 mmol) and H₂O (35 ml) were combined, cooled to 0° C. and thenadded in a single portion to the reaction. After stirring for 20 minutesat 0° C., the reaction was heated to 90° C. for 30 minutes and thenrecooled to 0° C. The pH was adjusted to ˜7 by dropwise addition ofconcentrated HCl. The solid was collected, washed with EtOAc, and thendried in vacuo to provide acid A-3 as a white solid.

[1434]¹H NMR (300 MHz, D₂O) δ8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz),4.36 (m, 1H), 3.51 (dd, 1H, J=5Hz, 13Hz) 3.21 (m, 1H).

Ethyl 2(S)-(4-iodo-phenylsulfonylamino)-β-alanine-hydrochloride (A-4)

[1435] HCl gas was rapidly bubbled through a suspension of acid A-3 (4.0g, 10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bathwas removed and the reaction was heated to 60° C. After 18 h, thereaction was concentrated to provide ester A-4 as a white solid.

[1436]¹H NMR (300 MHz, CD₃OD) δ7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz),4.25 (q, 1H, J=5Hz), 3.92 (m, 2H), 3.33 (m, 1H), 3.06 (m, 1H), 1.01 (t,3H, J=7Hz).

Ethyl 4-[2-(2-Aminopyridin-6-yl)ethyl]benzoate (A-5a)

[1437] A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation,see: Scheme 29 of PCT International Application Publication No. WO95/32710, published Dec. 7, 1995) 10% Pd/C (350 mg) and EtOH werestirred under 1 atm H₂. After 20 h, the reaction was filtered through acelite pad and then concentrated to provide ester A-5a as a brown oil.

[1438] TLC R_(f)=0.23 (silica, 40% EtOAc/hexanes). ¹H NMR (300 MHz,CDCl₃) δ7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, 1H, J=7Hz), 6.35 (d,1H, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H,J=7Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoic acid hydrochloride (A-6)

[1439] A suspension of ester A-5a (625 mg, 2.31 mmol) in 6N HCl (12 ml)was heated to 60° C. After ˜20 h, the reaction was concentrated to giveacid A-6 as a tan solid.

[1440]¹H NMR (300 MHz, CD₃OD) δ7.96 (d, 2H, J=8Hz), 7.80 (m, 1H), 7.33(d, 2H, J=8Hz), 6.84 (d, 1H, J=9Hz), 6.69 (d, 1H, J=7Hz), 3.09 (m, 4H).

Ethyl4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodo-phenylsulfonylamino)-β-alanine(A-7)

[1441] A solution of acid 15-6 (400 mg, 1.43 mmol), amine A-4 (686 mg,1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632μl, 5.72 mmol) in DMF (10 ml) was stirred for ˜20 h. The reaction wasdiluted with EtOAc and then washed with sat. NaHCO₃, brine, dried(MgSO₄) and concentrated. Flash chromatography (silica, EtOAc then 5%isopropanol/EtOAc) provided amide A-7 as a white solid.

[1442] TLC R_(f)=0.4 (silica, 10% isopropanol/EtOAc). ¹H NMR (300 MHz,CD₃OD) δ7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 (d, 2H, J=9Hz),7.29 (m, 1H), 7.27 (d, 2H, J=8Hz), 4.20 (m, 1H), 3.95 (q, 2H, J=7Hz),3.66 (dd, 1H, J=6Hz, 14Hz), 3.49 (dd, 1H, J=8Hz, 13Hz), 3.01 (m, 2H),2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-(4-iodophenyl-sulfonylamino)-β-alanine(A-8)

[1443] A solution of ester A-7 (200 mg, 0.3213 mmol) and 6N HCl (30 ml)was heated to 60° C. After ˜20 h, the reaction mixture was concentrated.Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/NH₄OH/H₂O) providedacid A-8 as a white solid.

[1444] TLC R_(f)=0.45 (silica, 20:20:1:1 EtOAc/EtOH/NH₄OH/H₂O). ¹H NMR(400 MHz, DMSO) δ8.40 (m, 1H), 8.14 (Bs, 1H), 7.81 (d, 2H, J=8Hz), 7.62(d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, 1H, J=7Hz),6.25 (d, 1H, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, 1H), 3.35 (m, 2H), 2.97(m, 2H), 2.79 (m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl)benzoyl-2(S)-(4-trimethylstannyl-phenylsulfonylamino-β-alanine(A-9)

[1445] A solution of iodide A-8 (70 mg, 0.1178 mmol), [(CH₃)₃Sn]₂ (49μl, 0.2356 mmol), Pd(PPh₃)₄ (5 mg) and dioxane (7 ml) was heated to 90°C. After 2 h, the reaction was concentrated and then purified bypreparative HPLC (Delta-Pak C₁₈ 15 μM 100A°, 40×100 mm; 95:5 then 5:95H₂O/CH₃CN) to provide the trifluoroacetate salt. The salt was suspendedin H₂O (10 ml), treated with NH₄OH (5 drops) and then lyophilized toprovide amide A-9 as a white solid.

[1446]¹H NMR (400 MHz, DMSO) δ8.40 (m, 1H), 8.18 (d, 1H, J=8Hz), 7.67(m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H),6.45 (bs, 2H), 4.00 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.97 (m, 2H),2.86 (m, 2H).

4-[2-(2-Aminopyridin-6-yl)ethyl]benzoyl-2(S)-4-¹²⁵iodo-phenylsulfonylamino-β-alanine(A-10)

[1447] An iodobead (Pierce) was added to a shipping vial of 5 mCi ofNa¹²⁵I (Amersham, IMS30) and stirred for five minutes at roomtemperature. A solution of 0.1 mg of A-9 in 0.05 mL of 10% H₂SO₄/MeOHwas made and immediately added to the Na¹²⁵I/iodobead vial. Afterstirring for three minutes at room temperature, approximately 0.04-0.05mL of NH₄OH was added so the reaction mixture was at pH 6-7. The entirereaction mixture was injected onto the HPLC for purification [Vydacpeptide-protein C-18 column, 4.6×250 mm, linear gradient of 10%acetonitrile (0.1% (TFA):H₂O (0.1% TFA) to 90% acetonitrile (0.1%TFA):H₂O (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time ofA-10 is 17 minutes under these conditions. Fractions containing themajority of the radioactivity were pooled, lyophilized and diluted withethanol to give approximately 1 mCi of A-10, which coeluted on HPLCanalysis with an authentic sample of A-8.

[1448] The following additional but non-limiting examples were preparedusing the procedures described above and are accompanied by their massspectral characterization data:

[1449] (1)3(R)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid; 433

[1450]3-(Quinolin-3-yl)-3-(7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoylamino)-propionicacid bis(trifluoroacetate); 461

[1451]3-(Quinolin-3-yl)-3-(6-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-hexanoylamino)-propionicacid; 447

[1452]3(S)-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-pent-4-enoicacid; 332

[1453]2-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate salt; 400

[1454]3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethylsulfanyl)propionylamino]-propionicacid bis(trifluoroacetate); 442

[1455]2(S)-(Benzenesulfonylamino)-10-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-decanoicacid; 460

[1456]2(S)-(Benzenesulfonylamino)-8-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-octanoicacid; 432

[1457]2(S)-(Cyclohexylmethaneslfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride; 466

[1458]2(S)-(7,7-Dimethyl-2-oxo-bicyclo[2.2.1]hept-1(S)-ylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride; 520

[1459]2(S)-(Phenylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 460

[1460]2(S)-(Cyclohexanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride; 452

[1461]2(S)-(3-Benzylureido)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 439

[1462]2(S)-(Benzyloxycarbonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 440

[1463]2(S)-(Phenylacetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 424

[1464] 2(S)-(Acetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid;348

[1465]2(S)-(Benzoylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 410

[1466]3-(Quinolin-3-yl)-7-[acetyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid; 461

[1467]3-(Quinolin-3-yl)-7-[methanesulfonyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid; 497

[1468]3-(6-Oxo-1,6-dihydro-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid bis-(trifluoroacetate); 384

[1469]3-(Quinolin-3-yl)-7-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]-naphthyridin-8-yl)-heptanoicacid bis(hydrochloride); 444

[1470]3-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid; 368

[1471]3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid trifluoroacetate; 407

[1472]2-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid bis(trifluoroacetate); 444

[1473] Compounds I-XXX whose structures are shown below can also beprepared as described above and depicted in Schemes 1-29 using syntheticmethodologies or variations thereon which are known and understood bythose skilled in the art of synthetic organic chemistry:

[1474] Instrumentation: Analytical and preparative HPLC was carried outusing a Waters 600E Powerline Multi Solvent Delivery System with 0.1 mLheads with a Rheodyne 7125 injector and a Waters 990 Photodiode ArrayDetector with a Gilson FC203 Microfraction collector. For analytical andpreparative HPLC, a Vydac peptide-protein C-18 column, 4.6×250 mm wasused with a C-18 Brownlee modular guard column. The acetonitrile usedfor the HPLC analyses was Fisher Optima grade. The HPLC radiodetectorused was a Beckman 170 Radioisotope detector. A Vydac C-18 protein andpeptide column, 3.9×250 mm was used for analytical and preparative HPLC.Solutions of radioactivity were concentrated using a Speedvac vacuumcentrifuge. Calibration curves and chemical concentrations weredetermined using a Hewlett Packard Model 8452A UVNis Diode ArraySpectrophotometer. Sample radioactivities were determined in a PackardA5530 gamma counter.

[1475] The test procedures employed to measure αvβ3 and αvβ5 binding andthe bone resorption inhibiting activity of the compounds of the presentinvention are described below.

BONE RESORPTION-PIT ASSAY

[1476] When osteoclasts engage in bone resorption, they can cause theformation of pits in the surface of bone that they are acting upon.Therefore, when testing compounds for their ability to inhibitosteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.

[1477] Consecutive 200 micron thick cross sections from a 6 mm cylinderof bovine femur diaphysis are cut with a low speed diamond saw (Isomet,Beuler, Ltd., Lake Bluff, Ill.). Bone slices are pooled, placed in a 10%ethanol solution and refrigerated until further use.

[1478] Prior to experimentation, bovine bone slices are ultrasonicatedtwice, 20 minutes each in H₂O. Cleaned slices are placed in 96 wellplates such that two control lanes and one lane for each drug dosage areavailable. Each lane represents either triplicate or quadruplicatecultures. The bone slices in 96 well plates are sterilized by UVirradiation. Prior to incubation with osteoclasts, the bone slices arehydrated by the addition of 0.1 ml αMEM, pH 6.9 containing 5% fetalbovine serum and 1% penicillin/streptomycin.

[1479] Long bones from 7-14 day old rabbits (New Zealand White Hare) aredissected, cleaned of soft tissue and placed in αMEM containing 20 mMHEPES. The bones are minced using scissors until the pieces are <1 mmand transferred to a 50 ml tube in a volume of 25 ml. The tube is rockedgently by hand for 60 cycles, the tissue is sedimented for 1 min., andthe supernatant is removed. Another 25 ml of medium is added to thetissue and rocked again. The second supernatant is combined with thefirst. The number of cells is counted excluding erythrocytes (typically˜2×10⁷ cells/ml). A cell suspension consisting of 5×10⁶/ml in αMEMcontaining 5% fetal bovine serum, 10 nM 1,25(OH)₂D₃, andpencillin-streptomycin is prepared. 200 ml aliquots are added to bovinebone slices (200 mm×6 mm) and incubated for 2 hrs. at 37° C. in ahumidified 5% CO₂ atmosphere. The medium is removed gently with amicropipettor and fresh medium containing test compounds is added. Thecultures are incubated for 48 hrs., and assayed for c-telopeptide(fragments of the al chain of type I collagen) by Crosslaps for culturemedia (Herlev, Denmark).

[1480] Bovine bone slices are exposed to osteoclasts for 20-24 hrs andare processed for staining. Tissue culture media is removed from eachbone slice. Each well is washed with 200 ml of H₂O, and the bone slicesare then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate,pH 7.4. After fixation, any remaining cellular debris is removed by 2min. ultrasonication in the presence of 0.25 M NH₄OH followed by 2×15min ultrasonication in H₂O. The bone slices are immediately stained for6-8 min with filtered 1% toluidine blue and 1% borax.

[1481] After the bone slices have dried, resorption pits are counted intest and control slices. Resorption pits are viewed in a Microphot Fx(Nikon) fluorescence microscope using a polarizing Nikon IGS filtercube. Test dosage results are compared with controls and resulting IC₅₀values are determined for each compound tested.

[1482] The appropriateness of extrapolating data from this assay tomammalian (including human) disease states is supported by the teachingfound in Sato, M., et al, Journal of Bone and Mineral Research, Vol. 5,No. 1, pp. 31-40, 1990, which is incorporated by reference herein in itsentirety. This article teaches that certain bisphosphonates have beenused clinically and appear to be effective in the treatment of Paget'sdisease, hypercalcemia of malignancy, osteolytic lesions produced bybone metastases, and bone loss due to immobilization or sex hormonedeficiency. These same bisphosphonates are then tested in the resorptionpit assay described above to confirm a correlation between their knownutility and positive performance in the assay.

EIB ASSAY

[1483] Duong et al., J. Bone Miner. Res., 8: S378 (1993), describes asystem for expressing the human integrin αvβ3. It has been suggestedthat the integrin stimulates attachment of osteoclasts to bone matrix,since antibodies against the integrin, or RGD-containing molecules, suchas echistatin (European Publication 382 451), can effectively block boneresorption.

[1484] Reaction Mixture:

[1485] 1. 175 μl TBS buffer (50 mM Tris.HCl pH 7.2, 150 mM NaCl, 1% BSA,1 mM CaCl₂, 1 mM MgCl₂).

[1486] 2. 25 ml cell extract (dilute with 100 mM octylglucoside bufferto give 2000 cpm/25 μl).

[1487] 3. ¹²⁵I-echistatin (25 μl/50,000 cpm) (see EP 382 451).

[1488] 4. 25 μl buffer (total binding) or unlabeled echistatin(non-specific binding).

[1489] The reaction mixture was then incubated for 1 h at room temp. Theunbound and the bound αvβ3 were separated by filtration using a SkatronCell Harvester. The filters (prewet in 1.5% polyethyleneimine for 10mins) were then washed with the wash buffer (50 mM Tris HCl, 1 mMCaCl₂/MgCl₂, pH 7.2). The filter was then counted in a gamma counter.

SPA ASSAY MATERIALS

[1490] 1. Wheat germ agglutinin Scintillation Proximity Beads (SPA):Amersham

[1491] 2. Octylglucopyranoside: Calbiochem

[1492] 3. HEPES: Calbiochem

[1493] 4. NaCl: Fisher

[1494] 5. CaCl₂: Fisher

[1495] 6. MgCl₂: SIGMA

[1496] 7. Phenylmethylsulfonylfluoride (PMSF): SIGMA

[1497] 8. Optiplate: PACKARD

[1498] 9. Compound A-10 (specific activity 500-1000 Ci/mmole)

[1499] 10. test compound

[1500] 11. Purified integrin receptor: αvβ3 was purified from 293 cellsoverexpressing αvβ3 (Duong et al., J. Bone Min. Res., 8:S378, 1993)according to Pytela (Methods in Enzymology, 144:475, 1987)

[1501] 12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mMCa²⁺/Mg²⁺, 0.5 mM PMSF

[1502] 13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE

[1503] 1. Pretreatment of SPA beads:

[1504] 500 mg of lyophilized SPA beads were first washed four times with200 ml of 50-OG buffer and once with 100 ml of binding buffer, and thenresuspended in 12.5 ml of binding buffer.

[1505] 2. Preparation of SPA beads and receptor mixture

[1506] In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads weresuspended in 97.5 μl of binding buffer and 20 ml of 50-OG buffer. 5 ml(˜30 ng/μl) of purified receptor was added to the beads in suspensionwith stirring at room temperature for 30 minutes. The mixture was thencentrifuged at 2,500 rpm in a Beckman GPR Benchtop centrifuge for 10minutes at 4° C. The pellets were then resuspended in 50 μl of bindingbuffer and 25 μl of 50-OG buffer.

[1507] 3. Reaction

[1508] The following were sequentially added into Optiplate incorresponding wells:

[1509] (i) Receptor/beads mixture (75 μl)

[1510] (ii) 25 μl of each of the following: compound to be tested,binding buffer for total binding or A-8 for non-specific binding (finalconcentration 1 μM)

[1511] (iii) A-10 in binding buffer (25 μl, final concentration 40 pM)

[1512] (iv) Binding buffer (125 μl)

[1513] (v) Each plate was sealed with plate sealer from PACKARD andincubated overnight with rocking at 4° C.

[1514] 4. Plates were counted using PACKARD TOPCOUNT

[1515] 5. % inhibition was calculated as follows:

[1516] A=total counts

[1517] B=nonspecific counts

[1518] C=sample counts

[1519] % inhibition =[{(A−B)−(C−B)}/(A−B)]/(A−B)×100

OCFORM ASSAY

[1520] Osteoblast-like cells (1.8 cells), originally derived from mousecalvaria, were plated in CORNING 24 well tissue culture plates in αMEMmedium containing ribo- and deoxyribonucleosides, 10% fetal bovine serumand penicillin-streptomycin. Cells were seeded at 40,000/well in themorning. In the afternoon, bone marrow cells were prepared from six weekold male Balb/C mice as follows:

[1521] Mice were sacrificed, tibiae removed and placed in the abovemedium. The ends were cut off and the marrow was flushed out of thecavity into a tube with a 1 mL syringe with a 27.5 gauge needle. Themarrow was suspended by pipetting up and down. The suspension was passedthrough >100 mm nylon cell strainer. The resulting suspension wascentrifuged at 350×g for seven minutes. The pellet was resuspended, anda sample was diluted in 2% acetic acid to lyse the red cells. Theremaining cells were counted in a hemacytometer. The cells were pelletedand resuspended at 1×10⁶ cells/mL. 50 μL was added to each well of 1.8cells to yield 50,000 cells/well and 1,25-dihydroxy-vitamin D₃ (D₃) wasadded to each well to a final concentration of 10 nM. The cultures wereincubated at 37° C. in a humidified, 5% CO₂ atmosphere. After 48 h, themedium was changed. 72 h after the addition of bone marrow, testcompounds were added with fresh medium containing D₃ to quadruplicatewells. Compounds were added again after 48 h with fresh mediumcontaining D₃. After an additional 48 h., the medium was removed, cellswere fixed with 10% formaldehyde in phosphate buffered saline for 10minutes at room temperature, followed by a 1-2 minute treatment withethanol:acetone (1:1) and air dried. The cells were then stained fortartrate resistant acid phosphatase as follows:

[1522] The cells were stained for 10-15 minutes at room temperature with50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mLFast Red Violet LB Salt and 0.1 mg/mL Naphthol AS-MX phosphate. Afterstaining, the plates were washed extensively with deionized water andair dried. The number of multinucleated, positive staining cells wascounted in each well.

αvβ5 ATTACHMENT ASSAY

[1523] Duong et al., J. Bone Miner. Res., 11: S290 (1996), describes asystem for expressing the human αvβ5 integrin receptor.

[1524] Materials:

[1525] 1. Media and solutions used in this assay are purchased fromBRL/Gibco, except BSA and the chemicals are from Sigma.

[1526] 2. Attachment medium: HBSS with 1 mg/ml heat-inactivated fattyacid free BSA and 2 mM CaCl₂.

[1527] 3. Glucosaminidase substrate solution: 3.75 mM p-nitrophenylN-acetyl-beta-D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH5.0.

[1528] 4. Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH10.5.

[1529] Methods:

[1530] 1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4°C. with human vitronectin (3 μg/ml) in 50 mM carbonate buffer (pH 9/.6),using 100 μl/well. Plates were then washed 2× with DPBS and blocked with2% BSA in DPBS for 2 h at room temperature. After additional washes (2×)with DPBS, plates were used for cell attachment assay.

[1531] 2. 293 (αvβ5) cells were grown in αMEM media in presence of 10%fetal calf serum to 90% confluence. Cells were then lifted from disheswith 1× Trypsin/EDTA and washed 3× with serum free αMEM. Cells wereresuspended in attachment medium (3×10⁵ cells/ml).

[1532] 3. Test compounds were prepared as a series of dilutions at 2×concentrations and added as 50 μl/well. Cell suspension was then addedas 50 ml/well. Plates were incubated at 37° C. with 55 CO₂ for 1 hour toallow attachment.

[1533] 4. Non-adherent cells were removed by gently washing the plates(3×) with DPBS and then incubated with glucosaminidase substratesolution (100 μl/well), overnight at room temperature in the dark. Toquantitate cell numbers, standard curve of glucosaminidase activity wasdetermined for each experiment by adding samples of cell suspensiondirectly to wells containing the enzyme substrate solution.

[1534] 5. The next day, the reaction was developed by addition of 185μl/well of glycine/EDTA solution and reading absorbance at 405 nm usinga Molecular Devices V-Max plate reader. Average test absorbance values(4 wells per test samples) were calculated. Then, the number of attachedcells at each drug concentration was quantitated versus the standardcurve of cells using the Softmax program.

EXAMPLE OF A PHARMACEUTICAL FORMULATION

[1535] As a specific embodiment of an oral composition, 100 mg of any ofthe compounds of the present invention are formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gel capsule.

[1536] Representative compounds of the present invention were tested andfound to bind to human αvβ3 integrin. These compounds were generallyfound to have IC₅₀ values less than about 100 nM in the SPA assay.

[1537] Representative compounds of the present invention were tested andgenerally found to inhibit ≧50% the attachment of αvβ5 expressing cellsto plates coated with vitronectin at concentrations of about 1 μM.

[1538] While the invention has been described and illustrated inreference to certain preferred embodiments thereof, those skilled in theart will appreciate that various changes, modifications andsubstitutions can be made therein without departing from the spirit andscope of the invention. For example, effective dosages other than thepreferred doses as set forth hereinabove may be applicable as aconsequence of variations in the responsiveness of the mammal beingtreated for severity of bone disorders caused by resorption, or forother indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of the formula

wherein X is selected from the group consisting of

 a 5- or 6-membered monocyclic aromatic or nonaromatic ring systemhaving 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting ofN, O, and S wherein the ring nitrogen atoms are unsubstituted orsubstituted with one R¹ substituent and the ring carbon atoms areunsubstituted or substituted with one or two R¹ substituents, and  a 9-to 14-membered polycyclic ring system, wherein one or more of the ringsis aromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S whereinthe ring nitrogen atoms are unsubstituted or substituted with one R¹substituent and the ring carbon atoms are unsubstituted or substitutedwith one or two R¹ substituents; Y is selected from the group consistingof —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—NR⁴—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —(CH₂)_(m)—SO—(CH₂)_(n)—,—(CH₂)_(m)—SO₂—(CH₂)_(n)—, —(CH₂)_(m)—O—(CH₂)_(n)—O—(CH₂)_(p)—,—(CH₂)_(m)—O—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,—(CH₂)_(m)—NR⁴—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,—(CH₂)_(m)—O—(CH₂)_(n)—S—(CH₂)_(p)—,—(CH₂)_(m)—S—(CH₂)_(n)—S—(CH₂)_(p)—,—(CH₂)_(m)—NR⁴—(CH₂)_(n)—S—(CH₂)_(p)—,—(CH₂)_(m)—NR⁴—(CH₂)_(n)—O—(CH₂)_(p)—,—(CH₂)_(m)—S—(CH₂)_(n)—O—(CH₂)_(p)—, and—(CH₂)_(m)—S—(CH₂)_(n)—NR⁴—(CH₂)_(p)—, wherein any methylene (CH₂)carbon atom in Y, other than in R⁴, can be substituted by one or two R³substituents; Z is selected from the group consisting of

 —CH₂CH₂—, and —CH═CH—, wherein either carbon atom can be substituted byone or two R³ substituents; R¹ and R² are each independently selectedfrom the group consisting of hydrogen, halogen, C₁₋₁₀ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloheteroalkyl, C₃₋₈ cycloalkyl C₁₋₆ alkyl, C₃₋₈cycloheteroalkyl C₁₋₆ alkyl, aryl, aryl C₁₋₈ alkyl, amino, amino C₁₋₈alkyl, C₁₋₃ acylamino, C₁₋₃ acylamino C₁₋₈ alkyl, (C₁₋₆ alkyl)_(p)amino,(C₁₋₆ alkyl)_(p)amino C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkoxy C₁₋₆ alkyl,hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkoxycarbonyl C₁₋₆ alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy,hydroxy C₁₋₆ alkyl, C₁₋₆ alkyloxy-C₁₋₆ alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C₁₋₈ alkyl-S(O)_(p),(C₁₋₈ alkyl)_(p)aminocarbonyl, C₁₋₈ alkyloxycarbonylamino, (C₁₋₈alkyl)_(p)aminocarbonyloxy, (aryl C₁₋₈ alkyl)_(p)amino, (aryl)_(p)amino,aryl C₁₋₈ alkylsulfonylamino, and C₁₋₈ alkylsulfonylamino; or two R¹substituents, when on the same carbon atom, are taken together with thecarbon atom to which they are attached to form a carbonyl group; each R³is independently selected from the group consisting of hydrogen, aryl,C₁₋₁₀ alkyl, aryl-(CH₂)_(r)—O—(CH₂)_(s)—,aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—, aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—, aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,halogen, hydroxyl, oxo, trifluoromethyl, C₁₋₈ alkylcarbonylamino, arylC₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, C₁₋₆alkylcarbonyloxy, C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p)amino, amino C₁₋₆alkyl, arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC≡C—(CH₂)_(t)—, C₁₋₆ alkyl-C≡C—(CH₂)_(t)—, C₃₋₇cycloalkyl-C≡C—(CH₂)_(t)—, aryl-C≡C—(CH₂)_(t)—, C₁₋₆alkylaryl-C≡C—(CH₂)_(t)—, CH₂═CH—(CH₂)_(t)—, C₁₋₆alkyl-CH═CH—(CH₂)_(t)—, C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,aryl-CH═CH—(CH₂)_(t)—, C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—, C₁₋₆alkyl-SO₂—(CH₂)_(t)—, C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—, C₁₋₆ alkoxy, arylC₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,(aryl)_(p)amino, (aryl)_(p)amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p)amino,(aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl, arylcarbonyloxy, aryl C₁₋₆alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈alkylsulfonylamino, arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, arylC₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈alkoxycarbonylamino C₁₋₈ alkyl, aryloxycarbonylamino C₁₋₈ alkyl, arylC₁₋₈ alkoxycarbonylamino, aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈alkylcarbonylamino, C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, aryl C₁₋₆alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p)aminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p)aminocarbonylaminoC₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p)aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆alkyl, (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonylC₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and (aryl C₁₋₈alkyl)_(p)aminocarbonyl C₁₋₆ alkyl; or two R³ substituents, when on thesame carbon atom are taken together with the carbon atom to which theyare attached to form a carbonyl group or a cyclopropyl group, whereinany of the alkyl groups of R³ are either unsubstituted or substitutedwith one to three R¹ substituents, and provided that each R³ is selectedsuch that in the resultant compound the carbon atom or atoms to which R³is attached is itself attached to no more than one heteroatom; each R⁴is independently selected from the group consisting of hydrogen, aryl,aminocarbonyl, C₃₋₈ cycloalkyl, amino C₁₋₆ alkyl,(aryl)_(p)aminocarbonyl, (aryl C₁₋₅ alkyl)_(p)aminocarbonyl,hydroxycarbonyl C₁₋₆ alkyl, C₁₋₈ alkyl, aryl C₁₋₆ alkyl, (C₁₋₆alkyl)_(p)amino C₂₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p)amino C₂₋₆ alkyl, C₁₋₈alkylsulfonyl, C₁₋₈ alkoxycarbonyl, aryloxycarbonyl, aryl C₁₋₈alkoxycarbonyl, C₁₋₈ alkylcarbonyl, arylcarbonyl, aryl C₁₋₆alkylcarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, aminosulfonyl, C₁₋₈alkylaminosulfonyl, (aryl)_(p)aminosulfonyl, (aryl C₁₋₈alkyl)_(p)aminosulfonyl, arylsulfonyl, arylC₁₋₆ alkylsulfonyl, C₁₋₆alkylthiocarbonyl, arylthiocarbonyl, and aryl C₁₋₆ alkylthiocarbonyl,wherein any of the alkyl groups of R⁴ are either unsubstituted orsubstituted with one to three R¹ substituents; R⁵ and R⁶ are eachindependently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, aryl, aryl-(CH₂)_(r)—O—(CH₂)_(s)—,aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—, aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—, aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,halogen, hydroxyl, C₁₋₈ alkylcarbonylamino, aryl C₁₋₅ alkoxy, C₁₋₅alkoxycarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, C₁₋₆ alkylcarbonyloxy,C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p)amino, amino C₁₋₆ alkyl,arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC≡C—(CH₂)_(t)—, C₁₋₆ alkyl-C≡C—(CH₂)_(t)—, C₃₋₇cycloalkyl-C≡C—(CH₂)_(t)—, aryl-C≡C—(CH₂)_(t)—, C₁₋₆alkylaryl-C≡C—(CH₂)_(t)—, CH₂═CH—(CH₂)_(t)—, C₁₋₆alkyl-CH═CH—(CH₂)_(t)—, C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,aryl-CH═CH—(CH₂)_(t)—, C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—, C₁₋₆alkyl-SO₂—(CH₂)_(t)—, C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—, C₁₋₆ alkoxy, arylC₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,(aryl)_(p)amino, (aryl)_(p)amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p)amino,(aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl, arylcarbonyloxy, aryl C₁₋₆alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈alkylsulfonylamino, arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, arylC₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈alkoxycarbonylamino C₁₋₈ alkyl, aryloxycarbonylamino C₁₋₈ alkyl, arylC₁₋₈ alkoxycarbonylamino, aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈alkylcarbonylamino, C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, aryl C₁₋₆alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p)aminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p)aminocarbonylaminoC₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p)aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylamino C₁₋₆alkyl, (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonylC₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, and (aryl C₁₋₈alkyl)_(p)aminocarbonyl C₁₋₆ alkyl; or R⁵ and R⁶ are taken together withthe carbon atom to which they are attached to form a carbonyl group,wherein any of the alkyl groups of R⁵ or R⁶ are either unsubstituted orsubstituted with one to three R¹ substituents, and provided that each R⁵and R⁶ are selected such that in the resultant compound the carbon atomto which R⁵ and R⁶ are attached is itself attached to no more than oneheteroatom; R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, aryl, aryl-(CH₂)_(r)—O—(CH₂)_(s)—,aryl-(CH₂)_(r)S(O)_(p)—(CH₂)_(s)—, aryl-(CH₂)_(r)—C(O)—(CH₂)_(s)—,aryl-(CH₂)_(r)—C(O)—N(R⁴)—(CH₂)_(s)—,aryl-(CH₂)_(r)—N(R⁴)—C(O)—(CH₂)_(s)—, aryl-(CH₂)_(r)—N(R⁴)—(CH₂)_(s)—,halogen, hydroxyl, C₁₋₈ alkylcarbonylamino, aryl C₁₋₅ alkoxy, C₁₋₅alkoxycarbonyl, (C₁₋₈ alkyl)_(p)aminocarbonyl, C₁₋₆ alkylcarbonyloxy,C₃₋₈ cycloalkyl, (C₁₋₆ alkyl)_(p)amino, amino C₁₋₆ alkyl,arylaminocarbonyl, alyl C₁₋₅ alkylaminocarbonyl, aminocarbonyl,aminocarbonyl C₁₋₆ alkyl, hydroxycarbonyl, hydroxycarbonyl C₁₋₆ alkyl,HC≡C—(CH₂)_(t)—, C₁₋₆ alkyl-C≡C—(CH₂)_(t)—, C₃₋₇cycloalkyl-C≡C—(CH₂)_(t)—, aryl-C≡C—(CH₂)_(t)—, C₁₋₆alkylaryl-C≡C—(CH₂)_(t)—, CH₂═CH—(CH₂)_(t)—, C₁₋₆alkyl-CH═CH—(CH₂)_(t)—, C₃₋₇ cycloalkyl-CH═CH—(CH₂)_(t)—,aryl-CH═CH—(CH₂)_(t)—, C₁₋₆ alkylaryl-CH═CH—(CH₂)_(t)—, C₁₋₆alkyl-SO₂—(CH₂)_(t)—, C₁₋₆ alkylaryl-SO₂—(CH₂)_(t)—, C₁₋₆ alkoxy, arylC₁₋₆ alkoxy, aryl C₁₋₆ alkyl, (C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl,(aryl)_(p)amino, (aryl)_(p)amino C₁₋₆ alkyl, (aryl C₁₋₆ alkyl)_(p)amino,(aryl C₁₋₆ alkyl)_(p)amino C₁₋₆ alkyl, arylcarbonyloxy, aryl C₁₋₆alkylcarbonyloxy, (C₁₋₆ alkyl)_(p)aminocarbonyloxy, C₁₋₈alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, C₁₋₈alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl, C₁₋₈alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl,aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino, arylC₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₁₋₆ alkyl,arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, aryl C₁₋₆alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl,arylaminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino, (C₁₋₈alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl, (aryl)_(p)aminocarbonylaminoC₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl,(C₁₋₈ alkyl)_(p)aminosulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonyl C₁₋₆ alkyl,arylsulfonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonyl, aryl C₁₋₆alkylsulfonyl C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyl C₁₋₆alkyl, arylcarbonyl C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonyl, aryl C₁₋₆alkylcarbonyl C₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆alkylthiocarbonylamino C₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl,aryl C₁₋₆ alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆alkyl, (C₁₋₈ alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, (aryl)_(p)aminocarbonylC₁₋₆ alkyl, (aryl C₁₋₈ alkyl)_(p)aminocarbonyl, (aryl C₁₋₈alkyl)_(p)aminocarbonyl C₁₋₆ alkyl, and C₇₋₂₀ polycyclyl C₀₋₈alkylsulfonylamino, wherein any of the alkyl groups of R⁷ and R⁸ areeither unsubstituted or substituted with one to three R¹ substituents,and provided that each R⁷ and R⁸ are selected such that in the resultantcompound the carbon atom to which R⁷ and R⁸ are attached is itselfattached to no more than one heteroatom; R⁹ is selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, aryl, aryl C₁₋₈ alkyl, C₁₋₈alkylcarbonyloxy C₁₋₄ alkyl, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyl, C₁₋₈alkylaminocarbonylmethylene, and C₁₋₈ dialkylaminocarbonylmethylene;wherein each m is independently an integer from 0 to 6; each n isindependently an integer from 0 to 6; each p is independently an integerfrom 0 to 2; each r is independently an integer from 1 to 3; each s isindependently an integer from 0 to 3; and each t is independently aninteger from 0 to 3; and the pharmaceutically acceptable salts thereof.2. The compound of claim 1 wherein X is a 6-membered monocyclic aromaticring system having 1 or 2 nitrogen atoms wherein each ring carbon atomis unsubstituted or substituted with one R¹ substituent, or a 9- to14-membered polycyclic ring system, wherein one or more of the rings isaromatic, and wherein the polycyclic ring system has 0, 1, 2, 3 or 4heteroatoms selected from the group consisting of N, O, and S, andwherein the ring nitrogen atoms are unsubstituted or substituted withone R¹ substituent and the ring carbon atoms are unsubstituted orsubstituted with one or two R¹ substituents.
 3. The compound of claim 2wherein X is selected from the group consisting of

and R¹ is as defined in claim 1 above.
 4. The compound of claim 3wherein X is

and R¹ is as defined in claim 1 above.
 5. The compound of claim 3wherein Y is selected from the group consisting of —(CH₂)_(m),—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—NR⁴—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —(CH₂)_(m)—SO—(CH₂)_(n)—,—(CH₂)_(m)—SO₂—(CH₂)_(n)—, —(CH₂)_(m)—O—(CH₂)_(n)—O—(CH₂)_(p)—,—(CH₂)_(m)—O—(CH₂)_(n)—NR⁴—(CH₂)_(p)—,—(CH₂)_(m)—NR⁴—(CH₂)_(n)—NR⁴—(CH₂)_(p)—, and—(CH₂)_(m)—NR⁴—(CH₂)_(n)—O—(CH₂)_(p)—, wherein any methylene (CH₂)carbon atom in Y, other than in R⁴, can be substituted by one or two R³substituents; and Z is selected from the group consisting of

—CH₂CH₂—, and —CH═CH—, wherein either carbon atom can be substituted byone or two R³ substituents.
 6. The compound of claim 5 wherein Y isselected from the group consisting of (CH₂)_(m), (CH₂)_(m)—S—(CH₂)_(n),and (CH₂)_(m)—NR⁴—(CH₂)_(n), wherein any methylene (CH₂) carbon atom inY, other than in R⁴, can be substituted by one or two R³ substituents;and Z is selected from the group consisting of

—CH₂CH₂—, wherein either carbon atom can be substituted by one or two R³substituents.
 7. The compound of claim 6 wherein each R³ isindependently selected from the group consisting of hydrogen, fluoro,trifluoromethyl, aryl, C₁₋₈ alkyl, arylC₁₋₆ alkyl hydroxyl, oxo,arylaminocarbonyl, aryl C₁₋₅ alkylaminocarbonyl, aminocarbonyl, andaminocarbonyl C₁₋₆ alkyl; and each R⁴ is independently selected from thegroup consisting of hydrogen, aryl, C₃₋₈ cycloalkyl, C₁₋₈ alkyl, C₁₋₈alkylcarbonyl, arylcarbonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl,arylC₁₋₆alkylsulfonyl, arylC₁₋₆alkylcarbonyl, C₁₋₈alkylaminocarbonyl,arylC₁₋₅alkylaminocarbonyl, arylC₁₋₈alkoxycarbonyl, andC₁₋₈alkoxycarbonyl.
 8. The compound of claim 7 wherein R⁶, R⁷, and R⁸are each hydrogen and R⁵ is selected from the group consisting ofhydrogen, aryl, C₁₋₈ alkyl, aryl-C≡C—(CH₂)_(t)—, aryl C₁₋₆ alkyl,CH₂═CH—(CH₂)_(t)—, and HC≡C—(CH₂)_(t)—.
 9. The compound of claim 8wherein R⁹ is selected from the group consisting of hydrogen, methyl,and ethyl.
 10. The compound of claim 9 wherein R⁹ is hydrogen.
 11. Thecompound of claim 7 wherein R⁵, R⁶, and R⁸ are each hydrogen and R⁷ isselected from the group consisting of hydrogen, aryl, C₁₋₈alkylcarbonylamino, C₁₋₈ alkylsulfonylamino, arylcarbonylamino,arylsulfonylamino, C₁₋₈ alkylsulfonylamino C₁₋₆ alkyl, arylsulfonylaminoC₁₋₆ alkyl, aryl C₁₋₆ alkylsulfonylamino, aryl C₁₋₆ alkylsulfonylaminoC₁₋₆ alkyl, C₁₋₈ alkoxycarbonylamino, C₁₋₈ alkoxycarbonylamino C₁₋₈alkyl, aryloxycarbonylamino C₁₋₈ alkyl, aryl C₁₋₈ alkoxycarbonylamino,aryl C₁₋₈ alkoxycarbonylamino C₁₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₁₋₆alkyl, arylcarbonylamino C₁₋₆ alkyl, aryl C₁₋₆ alkylcarbonylamino, arylC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl, aminocarbonylamino C₁₋₆ alkyl, (C₁₋₈alkyl)_(p)aminocarbonylamino, (C₁₋₈ alkyl)_(p)aminocarbonylamino C₁₋₆alkyl, (aryl)_(p)aminocarbonylamino C₁₋₆ alkyl, arylaminocarbonylamino,(aryl C₁₋₈ alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈alkyl)_(p)aminocarbonylamino C₁₋₆ alkyl, aminosulfonylamino C₁₋₆ alkyl,(C₁₋₈ alkyl)_(p)amino sulfonylamino, (C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, (aryl)_(p)aminosulfonylamino C₁₋₆ alkyl, (aryl C₁₋₈alkyl)_(p)aminosulfonylamino, (aryl C₁₋₈ alkyl)_(p)aminosulfonylaminoC₁₋₆ alkyl, C₁₋₆ alkylthiocarbonylamino, C₁₋₆ alkylthiocarbonylaminoC₁₋₆ alkyl, arylthiocarbonylamino C₁₋₆ alkyl, aryl C₁₋₆alkylthiocarbonylamino, aryl C₁₋₆ alkylthiocarbonylamino C₁₋₆ alkyl, andC₇₋₂₀ polycyclyl C₀₋₈ alkylsulfonylamino.
 12. The compound of claim 11wherein R⁵, R⁶, and R⁸ are each hydrogen and R⁷ is selected from thegroup consisting of hydrogen, aryl, C₁₋₈ alkylcarbonylamino, aryl C₁₋₆alkylcarbonylamino, arylcarbonylamino, C₁₋₈ alkylsulfonylamino, arylC₁₋₆ alkylsulfonylamino, arylsulfonylamino, C₁₋₈ alkoxycarbonylamino,aryl C₁₋₈ alkoxycarbonylamino, arylaminocarbonylamino, (C₁₋₈alkyl)_(p)aminocarbonylamino, (aryl C₁₋₈ alkyl)_(p)aminocarbonylamino,(C₁₋₈ alkyl)_(p)aminosulfonylamino, and (aryl C₁₋₈alkyl)_(p)aminosulfonylamino.
 13. The compound according to claim 12wherein R⁹ is selected from the group consisting of hydrogen, methyl,and ethyl.
 14. The compound according to claim 13 wherein R⁹ ishydrogen.
 15. The compound of claim 7 selected from the group consistingof:3-(5-(5,6,7,8-Tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(S)-(5,6,7,8-Tetrahydroquinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid (trifluoroacetate);2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;3(S)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(R)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3-(Quinolin-3-yl)-3-(7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoylamino)-propionicacid bis(trifluoroacetate);3-(Quinolin-3-yl)-3-(6-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-hexanoylamino)-propionicacid;3(S)-(3-Fluorophenyl)-3-(4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylamino)-butyrylamino)-propionicacid bis(trifluoroacetate);3(S)-(5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-pent-4-enoicacid;3(S)-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;2-(3-Fluorophenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate salt;3(S)-(Benzo[1,3]dioxol-5-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(S)-(2-Oxo-2,3-dihydro-benzoxazol-6-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;3(S)-(3-Fluorophenyl)-3-{3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid;3(S)-(3-Fluorophenyl)-3-(2-{propyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino}-acetylamino)-propionicacid trifluoroacetate;3(S)-(3-Fluorophenyl)-3-(2-{phenethyl-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyl]-amino}-acetylamino)-propionicacid trifluoroacetate;3(S)-(3-Fluorophenyl)-3-{3(S)-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-pent-4-ynoylamino}-propionicacid;3(S)-(3-Fluorophenyl)-3-{3(S)-(3-fluorophenyl)-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid bis(trifluoroacetate);3(S)-(3-Fluoro-4-phenyl-phenyl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;2(S)-(2-Thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;3(S)-(3-Fluorophenyl)-3-{3-methyl-3-[(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylmethyl)-amino]-propionylamino}-propionicacid;3(S)-(3-Fluorophenyl)-3-{2-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethylamino]-acetylamino}-propionicacid;3(S)-(3-Fluorophenyl)-3{[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-ureido}-propionicacid;2(S)-(Methanesulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(R orS),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(S orR),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl-propionyl)-amino]propionicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethylsulfanyl)propionylamino]-propionicacid bis(trifluoroacetate);3-(Quinolin-3-yl)-7-[(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;3-(Quinolin-3-yl)-7-[acetyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;3-(Quinolin-3-yl)-7-[methanesulfonyl-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylmethyl)amino]-heptanoicacid;3-[5-(2-Amino-pyrimidin-4-yl)-pentanoylamino]-3(S)-(quinolin-3-yl)-propionicacid; 9-(5,6,7,8-Tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;2-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid bis(trifluoroacetate);2(S)-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(R)-(Benzenesulfonylamino)-9-(S,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Benzenesulfonylamino)-10-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-decanoicacid;2(S)-(Benzenesulfonylamino)-8-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-octanoicacid;2(S)-(Cyclohexylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;2(S)-(7,7-Dimethyl-2-oxo-bicyclo[2,2]hept-1(S)-ylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;2(S)-(Phenylmethanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Cyclohexanesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;2(S)-(Butane-1-sulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid hydrochloride;2(S)-(3-Benzylureido)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Benzyloxycarbonylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Phenylacetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Acetylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;2(S)-(Benzoylamino)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Quinolin-3-yl)-7-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]-naphthyridin-8-yl)-heptanoicacid bis(hydrochloride);6-Oxo-3-(quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(N-Oxo-quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid; 3-(Phenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid trifluoroacetate;3-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(R)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(R)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(S)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Methoxypyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(6-Methoxy-pyridin-3-yl)-5-oxo-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Methoxy-pyridin-3-yl)-5-oxo-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Methoxy-pyridin-3-yl)-5-oxo-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;3(R)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;3(S)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid trifluoroacetate;3-(2-Methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2-Methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2-Methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(2-Methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2-Methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2-Methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;3(R)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;3(S)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;3-(6-Oxo-1,6-dihydro-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid bis-(trifluoroacetate); and the pharmaceutically acceptable saltsthereof.
 16. The compound of claim 15 selected from the group consistingof:3(S)-(Pyridin-3-yl)-3-(5-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;2(S)-Benzenesulfonylamino-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;3(S)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;3(R)-(Quinolin-3-yl)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid;2(S)-(2-Thienylsulfonylamino)-3-(5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-pentanoylamino)-propionicacid trifluoroacetate;3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(R orS),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid; 3(S)-(2,3-Dihydro-benzofuran-6-yl)-3-[3-(1,2,3,4,6,7,8(S orR),9-octahydro-benzo[b][1,8]naphthyridin-8-yl)-propionylamino]-propionicacid;3(S)-(6-Methoxy-pyridin-3-yl)-3-[N-methyl-3-(1,2,3,4,6,7,8,9-octahydro-benzo[b][1,8]naphthyridin-8-yl-propionyl)-amino]propionicacid;3-[5-(2-Amino-pyrimidin-4-yl)-pentanoylamino]-3(S)-(quinolin-3-yl)-propionicacid;2-(Benzenesulfonylamino)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-non-4-enoicacid bis(trifluoroacetate); and the pharmaceutically acceptable saltsthereof.
 17. The compound of claim 15 selected from the group consistingof:3(R)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Quinolin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Benzo[b]thiophen-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(3-Fluorophenyl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-benzofuran-6-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid; 3(R)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-furo[3,2-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid; 3(R)-(F uro[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(S)-(Furo[2,3b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(R)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(S)-(2,3-Dihydro-furo[2,3-b]pyridin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Methoxy-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Methoxy-pyridin-3-yl)-5-oxo-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Methoxy-pyridin-3-yl)-5-oxo-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(Pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2-Methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2-Methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(2-Methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(2-Methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(S)-(6-Amino-pyridin-3-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid;3(R)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride;3(S)-(Benzo[b]thiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoicacid hydrochloride; and the pharmaceutically acceptable salts thereof.18. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition made by combining a compound according to claim 1 and apharmaceutically acceptable carrier.
 20. A process for making apharmaceutical composition comprising combining a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 21. The compositionof claim 18 which further comprises an active ingredient selected fromthe group consisting of a) an organic bisphosphonate or apharmaceutically acceptable salt or ester thereof, b) an estrogenreceptor modulator, c) a cytotoxic/antiproliferative agent, d) a matrixmetalloproteinase inhibitor, e) an inhibitor of epidexmal-derived,fibroblast-derived, or platelet-derived growth factors, f) an inhibitorof VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, h) acathepsin K inhibitor, and i) a prenylation inhibitor, such as afarnesyl transferase inhibitor or a geranylgeranyl transferase inhibitoror a dual farnesyl/geranylgeranyl transferase inhibitor; and mixturesthereof.
 22. The composition of claim 21 wherein said active ingredientis selected from the group consisting of a) an organic bisphosphonate ora pharmaceutically acceptable salt or ester thereof, b) an estrogenreceptor modulator, and c) a cathepsin K inhibitor; and mixturesthereof.
 23. The composition of claim 22 wherein said organicbisphosphonate or pharmaceutically acceptable salt or ester thereof isalendronate monosodium trihydrate.
 24. The composition of claim 21wherein said active ingredient is selected from the group consisting ofa) a cytotoxic/antiproliferative agent, b) a matrix metalloproteinaseinhibitor, c) an inhibitor of epidermal-derived, fibroblast-derived, orplatelet-derived growth factors, d) an inhibitor of VEGF, e) aninhibitor of Flk-1/DR, Flt-1, Tck/Tie-2, or Tie-1, and f) a cathepsin Kinhibitor; and mixtures thereof.
 25. A method of eliciting an integrinreceptor antagonizing effect in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of acompound according to claim
 1. 26. The method of claim 25 wherein theintegrin receptor antagonizing effect is an αvβ3 antagonizing effect.27. The method of claim 26 wherein the αvβ3 antagonizing effect isselected from the group consisting of inhibition of bone resorption,restenosis, angiogenesis, diabetic retinopathy, macular degeneration,inflammation, viral disease, tumor growth, and metastasis.
 28. Themethod of claim 27 wherein the αvβ3 antagonizing effect is theinhibition of bone resorption.
 29. The method of claim 25 wherein theintegrin receptor antagonizing effect is an αvβ5 antagonizing effect.30. The method of claim 29 wherein the αvβ5 antagonizing effect isselected from the group consisting of inhibition of restenosis,angiogenesis, diabetic retinopathy, macular degeneration, inflammation,tumor growth, and metastasis.
 31. The method of claim 25 wherein theintegrin receptor antagonizing effect is a dual αvβ3/αvβ5 antagonizingeffect.
 32. The method of claim 31 wherein the dual αvβ3/αvβ5antagonizing effect is selected from the group consisting of inhibitionof bone resorption, restenosis, angiogenesis, diabetic retinopathy,macular degeneration, inflammation, viral disease, tumor growth, andmetastasis.
 33. The method of claim 25 wherein the integrin receptorantagonizing effect is an αvβ6 antagonizing effect.
 34. The method ofclaim 33 wherein the αvβ6 antagonizing effect is selected from the groupconsisting of angiogenesis, inflammatory response, and wound healing.35. A method of eliciting an integrin receptor antagonizing effect in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the composition of claim
 18. 36. Amethod of treating or preventing a condition mediated by antagonism ofan integrin receptor in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of thecomposition of claim
 18. 37. A method of inhibiting bone resorption in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of the composition of claim
 18. 38. Amethod of inhibiting bone resorption in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of the composition of claim
 22. 39. A method of treating tumorgrowth in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of the composition of claim24.
 40. A method of treating tumor growth in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of a compound according to claim 1 in combination with radiationtherapy.